TW202345834A - Nlrp3 modulators - Google Patents

Abstract

Described herein are NLRP3 modulators and methods of utilizing NLRP3 modulators in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.

Description

NLRP3 modulator

The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is a key component of the innate immune response and inflammatory processes, and its aberrant activity is involved in genetic disorders such as cryptopyrin-associated cyclic syndrome (CAPS) and Pathogenic in complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. Current treatments for NLRP3-related diseases include biological agents targeting IL-1. Small molecule inhibitors of NLRP3 offer an attractive alternative to these biologic agents due to their potential for improved safety and patient comfort and compliance.

In one aspect, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof: Formula (I'); where: L is -C(R _9a )(R _9b )-, -C(O)- or -C(=N-OR ₁₆ )-; R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 ring Alkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O )OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ ) (R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O ) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ),- CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally undergo a , two or three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N (R ₁₀ ) (R ₁₁ ); or R ₁ and R ₂ combine to form a 4-, 5-, or 6-membered cycloalkyl ring; a 4-, 5-, or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; the 4-, 5- or 6-membered heterocycloalkyl ring; the 5- or 6-membered heteroaryl ring; or the benzene ring is optionally modified by one or two One or three R ₁₄ groups are substituted; or R ₂ and R ₃ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or a 6-membered heteroaryl ring; or a benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered Heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; or R ₃ and R ₄ combined to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5 - or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6- A membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; or R ₄ and R ₅ are combined to form 4-, 5- or a 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, wherein the 4-, 5- or 6-membered Cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; R ₆ for R _6a is selected from hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl, wherein C _1-6 alkyl and C _3-6 cycloalkyl are optionally separated by one, two or three R ₁₄ groups Substitution; or R _6a and R ₁₅ together form a bridge of -CH ₂ - or -CH ₂ CH ₂ -; R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 hetero Aryl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _{The 1-9} heteroaryl group is optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) group substitution; or R ₇ and R ₈ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6- Membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or the benzene ring is optionally substituted by one, two or three R ₁₄ groups; R _9a and R _9b are each independently selected from hydrogen, halogen, -OH, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy; each R ₁₀ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3 -6} cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne base, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, optionally with one, two or three selected from halogen, C _{1- 6} alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl The radical is substituted; each R ₁₁ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₂ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 Haloalkyl; each R ₁₃ is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, including C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycle Alkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl group substitutions; each R ₁₄ is independently selected from halogen, - CN, C _1-6 alkyl, C _1-6 haloalkyl _{, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl , C 6 -10} aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ ) (R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ) , -C(O)C(O) N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S (=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally modified by one, two or three selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) group substitution; each R ₁₅ is independently selected from halogen, side oxygen group, -CN, C _1-6 alkyl, C _1-6 haloalkyl, _{C 2-6 alkenyl, C 2-6 alkynyl} , C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aromatic group, C _1-9 heteroaryl group, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , - C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O )(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3 -6} cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally have one, two or three selected from halogen, -CN, C _1-6 Alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N (R ₁₀ ) (R ₁₁ ) group substitution; or two R ₁₅ together form -CH ₂ - or -CH ₂ CH ₂ - bridge; R ₁₆ is selected from hydrogen and C _1-6 alkyl; and n is 0, 1, 2, 3 or 4.

In another aspect, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: Formula (I); where: L is -C(R _9a )(R _9b )-, -C(O)- or -C(=N-OR ₁₆ )-; R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl Base, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O) OR ₁₀ 、-OC(O)N(R ₁₀ )(R ₁₁ )、-N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ )、-N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )( R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally replaced by one, Two or three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ); or R ₁ and R ₂ combine to form a 4-, 5-, or 6-membered cycloalkyl ring; a 4-, 5-, or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, where The 4-, 5- or 6-membered cycloalkyl ring; the 4-, 5- or 6-membered heterocycloalkyl ring; the 5- or 6-membered heteroaryl ring; or the benzene ring is optionally separated by one or two Or three R ₁₄ groups are substituted; or R ₂ and R ₃ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5-or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered hetero Aryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; or R ₃ and R ₄ combined to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or a 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered Heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or phenyl ring optionally substituted with one, two or three R ₁₄ groups; or R ₄ and R ₅ combined to form 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered ring Alkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; R ₆ for or ; R _6a is selected from hydrogen and C _1-6 alkyl optionally substituted by one, two or three R ₁₄ groups; R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _{1- 6} alkyl, C _1-6 haloalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _{C 2-9 heterocycloalkyl} , C _6-10 aryl and C _1-9 heteroaryl, including C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, _{C 3-6 cycloalkyl, C 2-9 heterocycloalkyl ,} C _{6- 10} aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N( R ₁₀ ) (R ₁₁ ) is substituted with a group; or R ₇ and R ₈ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6 -membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; R _9a and R _9b are each independently selected from hydrogen, halogen, -OH, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy; each R ₁₀ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from the group consisting of one, two or three Halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl group substitution; each R ₁₁ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₂ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₃ is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 hetero Cycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one, two or three selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl , C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl groups are substituted; each R ₁₄ is independently Selected from halogen, -CN, C _1-6 alkyl, C _{1-6 haloalkyl, C 2-6 alkenyl} , C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycle Alkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O) N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S (O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C( O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from halogen by one, two or three , -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N (R ₁₀ ) (R ₁₁ ) group substitution; each R ₁₅ is independently selected from halogen, side oxygen group , -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C( O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )- , S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally have one, two or three selected from halogen, -CN , C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N (R ₁₀ ) (R ₁₁ ) group substitution; R ₁₆ is selected from hydrogen and C _1-6 alkyl; and n is 0, 1, 2, 3 or 4.

In some embodiments, is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is optionally substituted with one, two or three R ₁₄ groups C _1-6 alkyl. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is an unsubstituted C _1-6 alkyl group. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is -CH ₃ .

In some embodiments, is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is

In some embodiments, it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _{1 -6} alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl And C _1-9 heteroaryl, wherein C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _{C 2-9 heterocycloalkyl} , C _{6 -10} aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N via one, two or three (R ₁₀ ) (R ₁₁ ) is substituted with a group. In some embodiments, it is a compound of formula (I') or (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C _1-6 alkane group and C _1-6 haloalkyl group. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen and C _1-6 alkyl. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are hydrogen. In some embodiments, is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is hydrogen and R ₈ is -CH ₃ . In some embodiments, is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is -CH ₃ and R ₈ is hydrogen. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are -CH ₃ .

In some embodiments, is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a 4-, 5- or 6-membered cycloalkane base ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4 -, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or phenyl ring, optionally substituted with one, two or three R ₁₄ groups. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted benzene ring.

In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 halogen Alkyl, -OR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ or -C(O)N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 halogen Alkyl or -OH. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OH. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen, halogen, C _1-6 alkyl, C _1-6 halogen Alkyl or -OR ₁₀ . In some embodiments, is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen, halogen, C _1-6 alkyl, C _1-6 halogen Alkyl, -OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl or C _1-6 haloalkyl. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen, halogen, C _1-6 alkyl, C _1-6 halogen Alkyl or -OR ₁₀ . In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen.

In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen, halogen, C _1-6 alkyl, C _1-6 halogen Alkyl, -OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen or C _1-6 alkyl. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R _9a )(R _9b )-. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R _9a is selected from hydrogen, halogen and C _1-6 alkyl. In some embodiments, is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R _9a is hydrogen. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R _9b is selected from hydrogen, halogen and -OH. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R _9b is -OH. In some embodiments, it is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(O)-.

In one aspect, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof: Formula (II); wherein: R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , - OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O )R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), - CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and - via one, two or three Substitution of N(R ₁₀ )(R ₁₁ ); or combination of R ₁ and R ₂ to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl Ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or a 6-membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; or R ₂ and R ₃ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5 - or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; or R ₃ and R ₄ combined to form 4 -, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- Or a 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring optionally via one, two or three R ₁₄ groups group substitution; or R ₄ and R ₅ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl group Ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene optionally substituted with one, two or three R ₁₄ groups; R ₆ is R _6a is selected from hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl, wherein C _1-6 alkyl and C _3-6 cycloalkyl are optionally separated by one, two or three R ₁₄ groups Substitution; or R _6a and R ₁₅ together form a bridge of -CH ₂ - or -CH ₂ CH ₂ -; R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 hetero Aryl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _{The 1-9} heteroaryl group is optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) group substitution; or R ₇ and R ₈ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6- Membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or the benzene ring is optionally substituted by one, two or three R ₁₄ groups; each R ₁₀ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one or two Or three selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _{6- 10} aryl and C _1-9 heteroaryl groups are substituted; each R ₁₁ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₂ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₃ is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 Cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one, two or three selected from halogen, C _1-6 alkyl, C ₁ -Substitution of _-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl groups; Each R ₁₄ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N (R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ) , -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N( R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N( R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one, two or Three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) are substituted; each R ₁₅ is independently selected from Halogen, side oxygen group, -CN, C _1-6 alkyl, C 1-6 haloalkyl, C _2-6 alkenyl, _{C 2-6 alkynyl, C 3-6 cycloalkyl ,} C _2-9 Heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC( O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C (O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ ) (R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ ) C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), among which C _1-6 alkyl and C _2-6 alkenyl , C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected by one, two or three Substituted from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ); or two R ₁₅ together form -CH ₂ - or - CH ₂ CH ₂ - bridge; and n is 0, 1, 2, 3 or 4.

In another aspect, provided herein is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof: Formula (III); wherein: R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , - OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O )R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), - CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and - via one, two or three Substitution of N(R ₁₀ )(R ₁₁ ); or combination of R ₁ and R ₂ to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl Ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or a 6-membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; or R ₂ and R ₃ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5 - or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; or R ₃ and R ₄ combined to form 4 -, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- Or a 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring optionally via one, two or three R ₁₄ groups group substitution; or R ₄ and R ₅ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl group Ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene optionally substituted with one, two or three R ₁₄ groups; R ₆ is or ; R _6a is selected from hydrogen and C _1-6 alkyl optionally substituted by one, two or three R ₁₄ groups; R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _{1- 6} alkyl, C _1-6 haloalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _{C 2-9 heterocycloalkyl} , C _6-10 aryl and C _1-9 heteroaryl, including C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, _{C 3-6 cycloalkyl, C 2-9 heterocycloalkyl ,} C _{6- 10} aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N( R ₁₀ ) (R ₁₁ ) is substituted with a group; or R ₇ and R ₈ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6 -membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; each R ₁₀ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, where C _1-6 Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl as appropriate With one, two or three selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl Substituted with groups of C _6-10 aryl and C _1-9 heteroaryl; each R ₁₁ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₂ is independently selected Selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₃ is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3- 6} cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, optionally with one, two or three selected from halogen, C _1-6 Alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl Substituted with a group; each R ₁₄ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 Cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C( O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O) OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S( O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkane base, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl as appropriate. One, two or three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) are substituted; each R ₁₅ is independently selected from halogen, side oxygen group, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl , C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one or two One or three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) are substituted; and n is 0, 1, 2, 3 or 4.

In some embodiments, is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is C optionally substituted with one, two or three R ₁₄ groups _1-6 alkyl. In some embodiments, it is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is an unsubstituted C _1-6 alkyl group. In some embodiments, it is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is -CH ₃ .

In some embodiments, is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, it is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is

In some embodiments, it is a compound of formula (II) or (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _{1- 6} alkyl, C _1-6 haloalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _{C 2-9 heterocycloalkyl} , C _6-10 aryl and C _1-9 heteroaryl, including C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, _{C 3-6 cycloalkyl, C 2-9 heterocycloalkyl ,} C _{6- 10} aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N( R ₁₀ )(R ₁₁ ) is substituted with a group. In some embodiments, it is a compound of formula (II) or (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C _1-6 alkyl and C _1-6 haloalkyl. In some embodiments, it is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen and C _1-6 alkyl. In some embodiments, it is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are hydrogen. In some embodiments, is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is hydrogen and R ₈ is -CH ₃ . In some embodiments, is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is -CH ₃ and R ₈ is hydrogen. In some embodiments, it is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are -CH ₃ .

In some embodiments, is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a 4-, 5- or 6-membered cycloalkyl group Ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4- , a 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, optionally substituted with one, two or three R ₁₄ groups. In some embodiments, it is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted benzene ring.

In some embodiments, it is a compound of formula (II) or (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl group, -OR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ or -C(O)N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (II) or (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl base or -OH. In some embodiments, it is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OH. In some embodiments, it is a compound of formula (II) or (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl Base OR -OR ₁₀ . In some embodiments, it is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen. In some embodiments, it is a compound of formula (II) or (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl group, -OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (II) or (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl or C _1-6 haloalkyl. In some embodiments, it is a compound of formula (II) or (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl Base OR -OR ₁₀ . In some embodiments, it is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen.

In some embodiments, it is a compound of formula (II) or (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl group, -OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen or C _1-6 alkyl.

In another aspect described herein, is a pharmaceutical composition comprising a compound of formula (I'), (I), (II) or (III) or a pharmaceutically acceptable salt or solvate thereof, and pharmaceutically acceptable excipients.

In some embodiments described herein, there is a method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (II) or ( III) Compound or pharmaceutically acceptable salt or solvate thereof. In some embodiments described herein, there is a method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (II) or ( III) A compound or a pharmaceutically acceptable salt or solvate thereof, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity and gout.

In some embodiments described herein, there is a method of treating liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (II) or (III). ) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments described herein, there is a method of treating liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (II) or (III). ) compound or a pharmaceutically acceptable salt or solvate thereof, wherein the liver disease is selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral Hepatitis and cirrhosis.

In some embodiments described herein, there is a method of treating a lung disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (II) or (III). ) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments described herein, there is a method of treating a lung disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (II) or (III). ) compound or a pharmaceutically acceptable salt or solvate thereof, wherein the lung disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis.

In some embodiments described herein, there is a method of treating a central nervous system disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments described herein, there is a method of treating a central nervous system disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (II) Or (III) a compound or a pharmaceutically acceptable salt or solvate thereof, wherein the central nervous system disease is selected from Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease Parkinson's disease, Huntington's disease, traumatic brain injury, ischemic stroke and reperfusion, hemorrhagic stroke, epilepsy and depression.

In some embodiments described herein, there is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I) , (II) or (III) compound or its pharmaceutically acceptable salt or solvate. In some embodiments described herein, there is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I) , (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof, wherein the inflammatory or autoimmune disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, inflammation Sexual enteropathy, Crohn's disease and ulcerative colitis.

In some embodiments described herein, there is a method of treating cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (II) or (III) Compound or pharmaceutically acceptable salt or solvate thereof. In some embodiments described herein, there is a method of treating cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (II) or (III) A compound or a pharmaceutically acceptable salt or solvate thereof, wherein the cardiovascular disease is atherosclerosis or stroke. Incorporate by reference

All publications, patents and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference.

cross reference

This application claims the rights and interests of U.S. Provisional Application No. 63/320,157 filed on March 15, 2022 and U.S. Provisional Application No. 63/356,415 filed on June 28, 2022, the full texts of each of which are incorporated by reference. are incorporated into this article. definition

In the context of the present invention, a number of terms should be utilized.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood in the art to which the subject matter is claimed. In the event that there are multiple definitions for a term herein, those in this section shall prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences (eg, sequences available in GenBank or other databases) mentioned herein are incorporated by reference. Where reference is made to a URL or other such identifier or address, it should be understood that such identifiers may change and specific information may come and go on the Internet, but equivalent information may be found by searching the Internet. References are provided to demonstrate the availability and public dissemination of this information.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting of any subject matter claimed. In this application, use of the singular includes the plural unless expressly stated otherwise. It is important to note that as used in this specification and the accompanying claims, the singular forms "a/an" and "the" include plural references unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless otherwise specified. Furthermore, the use of the term "including" and other forms such as "include/includes/included" is non-limiting.

The section headings used in this article are for organizational purposes only and should not be construed as limiting the subject matter stated.

Definitions of standard chemical terms can be found in reference works including (but not limited to) Carey and Sundberg, Advanced Organic Chemistry 4th Edition, Volumes A (2000) and B (2001), Plenum Press, New York. Unless otherwise specified, conventional mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology methods were used.

Unless specific definitions are provided, the nomenclature and experimental procedures and techniques used in connection with the analytical chemistry, synthetic organic chemistry, and medicinal chemistry described herein are art-recognized. Standard techniques are used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis and tissue culture and transformation (eg, electroporation, lipofection). Reactions and purification techniques may be performed, for example, using a kit of manufacturer's instructions or as commonly accomplished in the art or as described herein. The techniques and procedures described above may generally be performed using conventional methods and as described in the various general and more specific references cited and discussed throughout this specification.

It is to be understood that the methods and compositions described herein are not limited to the specific methods, protocols, cell lines, constructs and reagents described herein and may vary accordingly. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, and compositions described herein.

As used herein, C ₁ to C _x includes C ₁ to C ₂ , C ₁ to C ₃ . . . C ₁ to C _x . C ₁ to C _x refers to the number of carbon atoms constituting the designated moiety (excluding optional substituents).

"Alkyl" refers to a linear or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms and not containing unsaturation. In some embodiments, "alkyl" can have 1 to 6 carbon atoms (whenever it appears herein, numerical ranges such as "1 to 6" refer to each integer within the given range; for example, "1 "To 6 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although this definition also covers terms in which no numerical range is specified. the appearance of "alkyl"). Alkyl groups of compounds described herein may be designated "C ₁ -C ₆ alkyl" or similar designations. By way of example only, "C ₁ -C ₆ alkyl" indicates the presence of 1 to 6 carbon atoms in the alkyl chain, i.e. the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-propyl A group consisting of butyl, isobutyl, second butyl, third butyl, n-pentyl, isopentyl, neopentyl and hexyl. Alkyl groups may be substituted or unsubstituted. Depending on the structure, an alkyl group may be a monogroup or a diradical (ie, alkylene group).

"Alkoxy" refers to "-O-alkyl", where alkyl is as defined herein.

The term "alkenyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms and containing at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include -CH= _CH2 , -C( _CH3 )= _CH2 , -CH= _CHCH3 , -CH=C( _CH3 ) ₂ , and -C( _CH3 )= _CHCH3 . In some embodiments, alkenyl groups can have 2 to 6 carbons. Alkenyl groups may be substituted or unsubstituted. Depending on the structure, the alkenyl group may be a monogroup or a diradical (i.e., alkenyl group).

The term "alkynyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms and containing at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH ₃ , -C≡CCH ₂ CH ₃ and -C≡CCH ₂ CH ₂ CH ₃ . In some embodiments, an alkynyl group can have 2 to 6 carbons. Alkynyl groups may be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monogroup or a diradical (i.e., alkynyl).

"Amine" refers to the -NH ₂ group.

The term "alkylamine" or "alkylamino" refers to _the group -N(alkyl) _xHy , where alkyl is as defined herein and x and y are selected from the group x=1, y=1 and x=2, y=0. When x=2, the alkyl group and the nitrogen to which it is attached may optionally form a cyclic ring system. "Dialkylamino" refers to a -N(alkyl) ₂ group, where alkyl is as defined herein.

The term "aromatic" refers to a planar ring containing 4n+2 pi electrons with a delocalized pi electron system, where n is an integer. Aromatic rings can be formed from 5, 6, 7, 8, 9, or more than 9 atoms. Aromatics may be substituted as appropriate. The term "aromatic" includes both aryl (eg, phenyl, naphthyl) and heteroaryl (eg, pyridyl, quinolyl) groups.

As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. Aromatic rings can be formed from 5, 6, 7, 8, 9, or more than 9 carbon atoms. Aryl groups are optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. Depending on the structure, an aryl group can be a monogroup or a diradical (i.e., aryl).

"Carboxy" refers to -CO ₂ H. In some embodiments, the carboxyl moiety can be replaced by a "carboxylic acid biosimilar", which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as the carboxylic acid moiety. Carboxylic acid biosimilars have similar biological properties to carboxylic acid groups. Compounds having a carboxylic acid moiety may have the carboxylic acid moiety exchanged with a carboxylic acid biosimilar and have similar physical and/or biological properties when compared to carboxylic acid-containing compounds. For example, in one embodiment, a carboxylic acid biosimilar will ionize at physiological pH to approximately the same extent as the carboxylic acid group. Examples of biological analogues of carboxylic acids include (including but not limited to) and the like.

The term "cycloalkyl" refers to a monocyclic or polycyclic nonaromatic group in which each of the atoms forming the ring (ie, the backbone atoms) is a carbon atom. Cycloalkyl groups may be saturated or partially unsaturated. A cycloalkyl group can be fused to an aromatic ring (in which case the cycloalkyl group is bonded through a non-aromatic ring carbon atom). In some embodiments, cycloalkyl groups include groups with 3 to 10 ring atoms.

The term "heteroaryl" or "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. The N- containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the backbone atoms of the ring is a nitrogen atom.

"Heterocycloalkyl" or "heteroalicyclic" groups refer to cycloalkyl groups in which at least one backbone ring atom is a heteroatom selected from nitrogen, oxygen and sulfur. These groups may be fused to aryl or heteroaryl groups. The term heteroalicyclic also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyl groups have 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is related to the atoms (i.e., the backbone atoms of the heterocycloalkyl ring) that make up the heterocycloalkyl group. Including heteroatoms) the total number of different.

The term "halo" or "halogen" means fluorine, chlorine, bromine and iodine.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. The halogens can be the same or they can be different. Non-limiting examples of haloalkyl groups include _-CH2Cl , _-CF3 , _-CHF2 , _{-CH2CF3 , -CF2CF3 ,} and the like.

The terms "fluoroalkyl" and "fluoroalkoxy" each include alkyl and alkoxy groups substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyl groups include -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ , -CF 2 CF ₃ , -CF ₂ CF _{2 CF 3} , -CF(CH ₃ ) _3, and Similar. Non-limiting examples of fluoroalkoxy groups include -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCH ₂ CF ₃ , -OCF ₂ CF ₃ , -OCF ₂ CF ₂ CF ₃ , -OCF(CH ₃ ) ₂ and the like.

The term "heteroalkyl" refers to an alkyl group in which one or more backbone chain atoms are selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom(s) may be placed at any internal position within the heteroalkyl group. Examples include (but are not limited to) -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , - CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S-CH ₂ -CH _3. -CH ₂ -CH ₂ -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH ₂ -NH-OCH ₃ , -CH ₂ -O-Si( CH ₃ ) ₃ , -CH ₂ -CH=N-OCH ₃ and -CH=CH-N(CH ₃ )-CH ₃ . Furthermore, up to two heteroatoms may be consecutive, such as, for example, _-CH2- NH- _OCH3 and _-CH2- O-Si( _CH3 ) ₃ . Excluding many heteroatoms, "heteroalkyl" can have 1 to 6 carbon atoms.

The term "bond" or "single bond" refers to a chemical bond between two atoms or two parts when the atoms connected by the bond are considered to be parts of a larger substructure.

The term "moiety" refers to a specific portion or functional group of a molecule. Chemical moieties are generally identified as chemical entities embedded in or attached to a molecule.

As used herein, a substituent "R" by itself and without a numerical designation refers to a group selected from the group consisting of alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (through a ring-carbon bond (knot) and substituents of heterocycloalkyl.

"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur.

The term "optionally substituted" or "substituted" means that the mentioned group may be substituted by one or more further groups individually and independently selected from: alkyl, cycloalkyl, aryl, heteroaryl Base, heterocycloalkyl, -OH, alkoxy group, aryloxy group, alkylthio group, arylthio group, alkyl styrene, aryl styrene, alkyl styrene, aryl styrene, -CN, alkyne, C ₁ -C ₆ alkyl alkyne, halo, acyl, acyloxy, -CO ₂ H, -CO ₂ -alkyl, nitro, haloalkyl, fluoroalkyl and amine (including monosubstituted and Disubstituted amine groups (eg, -NH ₂ , -NHR, -N(R) ₂ ) and their protected derivatives). For example, optional substituents may be L ^s R ^s , where each L ^s is independently selected from bond, -O-, -C(=O)-, -S-, -S(=O) -, -S(=O) ₂ -, -NH-, -NHC(O)-, -C(O)NH-, S(=O) ₂ NH-, -NHS(=O) ₂ , -OC( O)NH-, -NHC(O)O-, -(C ₁ -C ₆ alkyl)- or -(C ₂ -C ₆ alkenyl)-; and each R ^s is independently selected from H, (C ₁ -C ₆ alkyl), (C ₃ -C ₈ cycloalkyl), aryl, heteroaryl, heterocycloalkyl and C ₁ -C ₆ heteroalkyl. Protecting groups that can form protected derivatives of the above substituents are found in sources such as Greene and Wuts (above).

As used herein, the term "about/approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

As used herein, the term "therapeutically effective amount" refers to an amount of an NLRP3 inhibitor that is effective to at least partially ameliorate or at least partially prevent the conditions or diseases described herein when administered to a mammal in need thereof.

As used herein, the term "expression" encompasses the process by which a polynucleotide is transcribed into mRNA and translated into a peptide, polypeptide or protein.

The term "modulation" encompasses a decrease or increase in activity or performance depending on the target molecule.

The term "activator" is used in this specification to mean any molecular substance that causes activation of a designated receptor, regardless of whether the substance itself binds to the receptor or a metabolite of the substance binds to the receptor when the substance is administered topically. receptor. Thus, the activator may be a ligand for the receptor or it may be an activator that is metabolized to the ligand of the receptor, ie, a metabolite that is formed in the tissue and is the actual ligand.

The term "patient" or "mammal" means a human, non-human primate, canine, feline, bovine, ovine, porcine, murine or other veterinary or laboratory mammal. Those skilled in the art know that therapy that reduces the severity of pathology in one mammal predicts the effect of the therapy in another mammal.

"Pharmaceutically acceptable salts" include both acid and base addition salts. Pharmaceutically acceptable salts of any of the compounds described herein are intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salts" means those salts which retain the biological effectiveness and properties of the free base, which are not biologically or inherently undesirable, and which are salts with inorganic acids such as hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid and the like) are formed. It also includes organic acids (such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanol acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.) and includes (For example) acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, formazan acid Salts formed from sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Exemplary salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chlorine Compound, bromide, iodide, acetate, trifluoroacetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate , fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, Tosylate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate and the like. Also included are salts of amino acids, such as arginates, gluconates, and galacturonates (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 ( 1997)). Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt.

"Pharmaceutically acceptable base addition salts" means those salts which retain the biological availability and properties of the free acid and which are not biologically or inherently required. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed using metals or amines such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins , for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine acid, Arginine, histine, caffeine, procaine, N,N -dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, betaine Diamine, ethyldiphenylamine, N -methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N -ethylpiperidine, polyamine resin and similar By. See Berge et al., supra.

As used herein, "treatment/treating" or "mitigation" or "improvement" are used interchangeably herein. These terms refer to methods of obtaining beneficial or desired results, including (but not limited to) therapeutic benefit and/or preventive benefit. "Therapeutic benefit" means the eradication or amelioration of the underlying condition being treated. Likewise, therapeutic benefit is achieved with the eradication or amelioration of one or more of the pathological symptoms associated with the underlying condition such that improvement is observed in the patient despite the fact that the patient still suffers from the underlying condition. For prophylactic benefit, the composition is administered to patients who are at risk of developing a particular disease, or to patients who report one or more pathological symptoms of the disease, although a diagnosis of the disease has not yet been made. NLRP3 modulator

NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental, and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing the apoptotic protease activation and recruitment domain (ASC). ASC then polymerizes to form large aggregates called ASC spots.

Polymerized ASC associates with the caspase-1 to form a complex called the inflammasome. This results in the activation of active apoptotic protease-1, which cleaves the precursor forms of the pro-inflammatory cytokines IL-1β and IL-18 (respectively known as pro-IL-1β and pro-IL-18), thereby activating these cells hormone. Apoptosis protease-1 also mediates a form of inflammatory cell death called pyroptosis. ASC speck aggregates can also recruit and activate apoptotic protease-8, which can process pro-IL-ίβ and pro-IL-18 and trigger apoptotic cell death.

Apoptotic protease-1 cleaves pro-IL-ίβ and pro-IL-18 into their active forms, which are secreted from the cells. Active apoptotic protease-1 also cleaves gasdermin-D to trigger apoptosis. Through its control of the pyroptotic cell death pathway, apoptotic protease-1 also mediates the release of alarmin molecules such as IL-33 and high mobility group 1 protein (HMGB1). Apoptotic protease-1 also cleaves intracellular IL-1R2, causing its degradation and allowing the release of IL-1α. In human cells, apoptotic protease-1 also controls the processing and secretion of IL-37. Many other apoptotic protein-1 substrates, such as components of the cytoskeleton and glycolytic pathways, can promote apoptotic protein-1-dependent inflammation.

NLRP3-dependent ASC specks are released into the extracellular environment, where they activate apoptotic protease-1, induce the processing of apoptotic protease-1 substrates, and propagate inflammation. Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury. For example, IL-1β signaling induces the secretion of the pro-inflammatory cytokines IL-6 and TNF. IL-1β and IL-18 synergize with IL-23 to induce IL-17 production by memory CD4 Th17 cells and by γδ T cells in the absence of T cell receptor engagement. IL-18 and IL-12 also synergistically induce the production of IFN-γ from memory T cells and NK cells, thereby driving Th1 responses.

The hereditary CAPS diseases Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal multisystem inflammatory disease (NOMID) are caused by gain-of-function mutations in NLRP3. NLRP3 is defined as a key component of the inflammatory process. NLRP3 has also been implicated in the pathogenesis of many complex diseases, especially metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout.

The role of NLRP3 in central nervous system diseases is emerging, and lung diseases have also been shown to be affected by NLRP3. In addition, NLRP3 has a role in the development of liver disease, kidney disease and aging. Many of these associations were defined using NLRP3 KO mice, but there are also insights into the specific activation of NLRP3 in these diseases. In type 2 diabetes (T2D), amylin deposition in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

Current treatments for NLRP3-related diseases include biological agents targeting IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody canakinumab, and the soluble IL1 receptor decoy rilonacept. These approaches have proven success in treating CAPS, and these biologic agents have been used in clinical trials for other IL-1β-related diseases. Small molecule inhibitors of NLRP3 offer an attractive alternative to these biologic agents due to their potential for improved safety (minimal risk of infection and ease of discontinuation compared with biologic agents) and patient comfort and compliance.

Compounds of formula (I'), (I), (Ia), (Ib), (II) or (III) described herein are NLRP3 modulators. Compounds of Formula (I'), (I), (Ia), (Ib), (II) or (III) described herein and compositions containing these compounds may be used to treat NLRP3-related diseases, including but not Limited to) type 2 diabetes, atherosclerosis, obesity and gout.

In some embodiments, provided herein is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof: Formula (I'); where: L is -C(R _9a )(R _9b )-, -C(O)- or -C(=N-OR ₁₆ )-; R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 ring Alkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O )OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ ) (R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O ) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ),- CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally undergo a , two or three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N (R ₁₀ ) (R ₁₁ ); or R ₁ and R ₂ combine to form a 4-, 5-, or 6-membered cycloalkyl ring; a 4-, 5-, or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; the 4-, 5- or 6-membered heterocycloalkyl ring; the 5- or 6-membered heteroaryl ring; or the benzene ring is optionally modified by one or two One or three R ₁₄ groups are substituted; or R ₂ and R ₃ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or a 6-membered heteroaryl ring; or a benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered Heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; or R ₃ and R ₄ combined to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5 - or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6- A membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; or R ₄ and R ₅ are combined to form 4-, 5- or a 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, wherein the 4-, 5- or 6-membered Cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; R ₆ for R _6a is selected from hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl, wherein C _1-6 alkyl and C _3-6 cycloalkyl are optionally separated by one, two or three R ₁₄ groups Substitution; or R _6a and R ₁₅ together form a bridge of -CH ₂ - or -CH ₂ CH ₂ -; R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 hetero Aryl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _{The 1-9} heteroaryl group is optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) group substitution; or R ₇ and R ₈ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6- Membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; R _9a and R _9b are each independently selected from hydrogen, halogen, -OH, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy; each R ₁₀ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3 -6} cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne base, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, optionally with one, two or three selected from halogen, C _{1- 6} alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl The radical is substituted; each R ₁₁ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₂ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 Haloalkyl; each R ₁₃ is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, including C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycle Alkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl group substitutions; each R ₁₄ is independently selected from halogen, - CN, C _1-6 alkyl, C _1-6 haloalkyl _{, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl , C 6 -10} aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ ) (R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ) , -C(O)C(O) N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S (=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally modified by one, two or three selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) group substitution; each R ₁₅ is independently selected from halogen, side oxygen group, -CN, C _1-6 alkyl, C _1-6 haloalkyl, _{C 2-6 alkenyl, C 2-6 alkynyl} , C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aromatic group, C _1-9 heteroaryl group, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , - C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O )(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3 -6} cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally have one, two or three selected from halogen, -CN, C _1-6 Alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N (R ₁₀ ) (R ₁₁ ) group substitution; or two R ₁₅ together form -CH ₂ - or -CH ₂ CH ₂ - bridge; R ₁₆ is selected from hydrogen and C _1-6 alkyl; and n is 0, 1, 2, 3 or 4.

In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R _9a )(R _9b )-. In some embodiments, is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R _9a )(R _9b )- and R _9a is selected from hydrogen, halogen, and C _1-6 alkyl. In some embodiments, is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R _9a )(R _9b )- and R _9b is selected from hydrogen, halogen and - OH. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH ₂ -. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(OH)-. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(CH ₃ )-. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(OH)(CH ₃ )-.

In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(O)-.

In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR ₁₆ )-. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OH)-. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR ₁₆ )- and R ₁₆ is C _1-6 alkyl.

In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is .

In some embodiments, is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is C _1-6 optionally substituted with one, two or three R ₁₄ groups alkyl. In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is an unsubstituted C _1-6 alkyl group. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is -CH ₃ . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is -CH ₂ CH ₃ . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is hydrogen. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R _is selected from . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is .

In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl , C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _{1- 9} heteroaryl, including C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ ) via one, two or three (R ₁₁ ) group substitution. In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C _1-6 alkyl and C _{1 -6} haloalkyl. In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen and C _1-6 alkyl. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are hydrogen. In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are C _1-6 alkyl. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are -CH ₃ . In some embodiments, is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is hydrogen and R ₈ is -CH ₃ . In some embodiments, is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is -CH ₃ and R ₈ is hydrogen.

In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a 4-, 5- or 6-membered cycloalkyl ring; 4 -, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or a 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring optionally substituted with one, two or three R ₁₄ groups. In some embodiments, is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound optionally substituted with one, two or three R ₁₄ groups The benzene ring. In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted benzene ring. In some embodiments, is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound optionally substituted with one, two or three R ₁₄ groups 5- or 6-membered heteroaryl ring. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 5- or 6-membered heteroaryl ring. In some embodiments, is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound optionally substituted with one, two or three R ₁₄ groups 4-, 5- or 6-membered heterocycloalkyl ring. In some embodiments, is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 4-, 5- or 6-membered heterocycloalkane base ring. In some embodiments, is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound optionally substituted with one, two or three R ₁₄ groups 4-, 5- or 6-membered cycloalkyl ring. In some embodiments, is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 4-, 5- or 6-membered cycloalkyl group ring.

In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, - OR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ or -C(O)N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or - OH. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OR ₁₀ . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OH. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is halogen. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is C _1-6 alkyl. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -CH ₃ . In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -CF ₃ .

In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or - OR ₁₀ . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is halogen. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is C _1-6 alkyl. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -CH ₃ . In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -CF ₃ . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -OR ₁₀ . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -OH.

In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, - OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl or C _1-6 haloalkyl. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -CH ₃ . In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -CF ₃ . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is halogen. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -OR ₁₀ . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -OH. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -N(R ₁₀ )(R ₁₁ ).

In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or - OR ₁₀ . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is halogen. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is C _1-6 alkyl. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -CH ₃ . In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -CF ₃ . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -OR ₁₀ . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -OH.

In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, - OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen or C _1-6 alkyl. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is C _1-6 alkyl. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -CH ₃ . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is halogen. In some embodiments, it is a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -CF ₃ . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -OR ₁₀ . In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -OH. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -N(R ₁₀ )(R ₁₁ ).

In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: Formula (I); where: L is -C(R _9a )(R _9b )-, -C(O)- or -C(=N-OR ₁₆ )-; R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl Base, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O) OR ₁₀ 、-OC(O)N(R ₁₀ )(R ₁₁ )、-N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ )、-N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )( R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally replaced by one, Two or three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ); or R ₁ and R ₂ combine to form a 4-, 5-, or 6-membered cycloalkyl ring; a 4-, 5-, or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, where The 4-, 5- or 6-membered cycloalkyl ring; the 4-, 5- or 6-membered heterocycloalkyl ring; the 5- or 6-membered heteroaryl ring; or the benzene ring is optionally separated by one or two Or three R ₁₄ groups are substituted; or R ₂ and R ₃ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5-or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered hetero Aryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; or R ₃ and R ₄ combined to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or a 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered Heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or phenyl ring optionally substituted with one, two or three R ₁₄ groups; or R ₄ and R ₅ combined to form 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered ring Alkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; R ₆ for or ; R _6a is selected from hydrogen and C _1-6 alkyl optionally substituted by one, two or three R ₁₄ groups; R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _{1- 6} alkyl, C _1-6 haloalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _{C 2-9 heterocycloalkyl} , C _6-10 aryl and C _1-9 heteroaryl, including C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, _{C 3-6 cycloalkyl, C 2-9 heterocycloalkyl ,} C _{6- 10} aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N( R ₁₀ ) (R ₁₁ ) is substituted with a group; or R ₇ and R ₈ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6 -membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; R _9a and R _9b are each independently selected from hydrogen, halogen, -OH, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy; each R ₁₀ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from the group consisting of one, two or three Halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl group substitution; each R ₁₁ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₂ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₃ is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 hetero Cycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one, two or three selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl , C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl groups are substituted; each R ₁₄ is independently Selected from halogen, -CN, C _1-6 alkyl, C 1-6 haloalkyl, C _2-6 alkenyl, _{C 2-6 alkynyl, C 3-6 cycloalkyl ,} C _2-9 heterocycle Alkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O) N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S (O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C( O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from halogen by one, two or three , -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N (R ₁₀ ) (R ₁₁ ) group substitution; each R ₁₅ is independently selected from halogen, side oxygen group , -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C( O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )- , S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally have one, two or three selected from halogen, -CN , C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N (R ₁₀ ) (R ₁₁ ) group substitution; R ₁₆ is selected from hydrogen and C _1-6 alkyl; and n is 0, 1, 2, 3 or 4.

In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R _9a )(R _9b )-. In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R _9a )(R _9b )- and R _9a is selected from hydrogen, halogen, and C _{1 -6} alkyl. In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R _9a )(R _9b )- and R _9b is selected from hydrogen, halogen and -OH . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is _-CH2- . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(OH)-. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(CH ₃ )-. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(OH)(CH ₃ )-.

In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(O)-.

In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR ₁₆ )-. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OH)-. In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR ₁₆ )- and R ₁₆ is C _1-6 alkyl.

In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is a C _1-6 alkane optionally substituted with one, two or three R ₁₄ groups base. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is an unsubstituted C _1-6 alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is -CH ₃ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is -CH ₂ CH ₃ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 Heteroaryl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl is optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )( R ₁₁ ) is substituted with a group. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C _1-6 alkyl and C _{1- 6} haloalkyl. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen and C _1-6 alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are hydrogen. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are C _1-6 alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are -CH ₃ . In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is hydrogen and R ₈ is -CH ₃ . In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is -CH ₃ and R ₈ is hydrogen.

In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a 4-, 5- or 6-membered cycloalkyl ring; 4- , 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5-or A 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, optionally substituted with one, two or three R ₁₄ groups. In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of Formula (I), optionally substituted with one, two or three R ₁₄ groups. benzene ring. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted benzene ring. In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of Formula (I), optionally substituted with one, two or three R ₁₄ groups. 5- or 6-membered heteroaryl ring. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 5- or 6-membered heteroaryl ring. In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of Formula (I), optionally substituted with one, two or three R ₁₄ groups. 4-, 5- or 6-membered heterocycloalkyl ring. In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 4-, 5- or 6-membered heterocycloalkyl ring. In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of Formula (I), optionally substituted with one, two or three R ₁₄ groups. 4-, 5- or 6-membered cycloalkyl ring. In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 4-, 5- or 6-membered cycloalkyl ring .

In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ or -C(O)N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OH . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OR ₁₀ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OH. In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein _R1 is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein _R1 is halogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is C _1-6 alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -CH ₃ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -CF ₃ .

In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OR ₁₀ . In some embodiments, is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein _R2 is halogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is C _1-6 alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -CH ₃ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -CF ₃ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -OR ₁₀ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -OH.

In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl or C _1-6 haloalkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -CH ₃ . In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -CF ₃ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is halogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -OR ₁₀ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -OH. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -N(R ₁₀ )(R ₁₁ ).

In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OR ₁₀ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is halogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is C _1-6 alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -CH ₃ . In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -CF ₃ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -OR ₁₀ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -OH.

In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen or C _1-6 alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is C _1-6 alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -CH ₃ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is halogen. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -CF ₃ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -OR ₁₀ . In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -OH. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -N(R ₁₀ )(R ₁₁ ).

In some embodiments, provided herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: Formula (Ia); where: L is -C(R _9a )(R _9b )-, -C(O)- or -C(=N-OR ₁₆ )-; R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl Base, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O) OR ₁₀ 、-OC(O)N(R ₁₀ )(R ₁₁ )、-N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ )、-N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )( R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally replaced by one, Two or three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ); or R ₁ and R ₂ combine to form a 4-, 5-, or 6-membered cycloalkyl ring; a 4-, 5-, or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, where The 4-, 5- or 6-membered cycloalkyl ring; the 4-, 5- or 6-membered heterocycloalkyl ring; the 5- or 6-membered heteroaryl ring; or the benzene ring is optionally separated by one or two Or three R ₁₄ groups are substituted; or R ₂ and R ₃ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5-or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered hetero Aryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; or R ₃ and R ₄ combined to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or a 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered Heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or phenyl ring optionally substituted with one, two or three R ₁₄ groups; or R ₄ and R ₅ combined to form 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered ring Alkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; R ₆ for ; R _6a is selected from hydrogen and C _1-6 alkyl optionally substituted by one, two or three R ₁₄ groups; R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _{1- 6} alkyl, C _1-6 haloalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _{C 2-9 heterocycloalkyl} , C _6-10 aryl and C _1-9 heteroaryl, including C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, _{C 3-6 cycloalkyl, C 2-9 heterocycloalkyl ,} C _{6- 10} aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N( R ₁₀ ) (R ₁₁ ) is substituted with a group; or R ₇ and R ₈ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6 -membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; R _9a and R _9b are each independently selected from hydrogen, halogen, -OH, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy; each R ₁₀ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from the group consisting of one, two or three Halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl group substitution; each R ₁₁ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₂ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₃ is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 hetero Cycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one, two or three selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl , C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl groups are substituted; each R ₁₄ is independently Selected from halogen, -CN, C _1-6 alkyl, C _{1-6 haloalkyl, C 2-6 alkenyl} , C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycle Alkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O) N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S (O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C( O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from halogen by one, two or three , -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N (R ₁₀ ) (R ₁₁ ) group substitution; each R ₁₅ is independently selected from halogen, side oxygen group , -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C( O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )- , S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally have one, two or three selected from halogen, -CN , C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N (R ₁₀ ) (R ₁₁ ) group substitution; R ₁₆ is selected from hydrogen and C _1-6 alkyl; and n is 0, 1, 2, 3 or 4.

In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R _9a )(R _9b )-. In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R _9a )(R _9b )- and R _9a is selected from hydrogen, halogen, and C _{1 -6} alkyl. In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R _9a )(R _9b )- and R _9b is selected from hydrogen, halogen and -OH . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is _-CH2- . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(OH)-. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(CH ₃ )-. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(OH)(CH ₃ )-.

In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(O)-.

In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR ₁₆ )-. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OH)-. In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR ₁₆ )- and R ₁₆ is C _1-6 alkyl.

In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is a C _1-6 alkane optionally substituted with one, two or three R ₁₄ groups base. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is an unsubstituted C _1-6 alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is -CH ₃ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is -CH ₂ CH ₃ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is hydrogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 Heteroaryl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl is optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )( R ₁₁ ) is substituted with a group. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C _1-6 alkyl and C _{1- 6} haloalkyl. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen and C _1-6 alkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are hydrogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are C _1-6 alkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are -CH ₃ . In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is hydrogen and R ₈ is -CH ₃ . In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is -CH ₃ and R ₈ is hydrogen.

In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a 4-, 5- or 6-membered cycloalkyl ring; 4- , 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5-or A 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, optionally substituted with one, two or three R ₁₄ groups. In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound optionally substituted with one, two or three R ₁₄ groups. benzene ring. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted benzene ring. In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound optionally substituted with one, two or three R ₁₄ groups. 5- or 6-membered heteroaryl ring. In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 5- or 6-membered heteroaryl ring. In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound optionally substituted with one, two or three R ₁₄ groups. 4-, 5- or 6-membered heterocycloalkyl ring. In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 4-, 5- or 6-membered heterocycloalkyl ring. In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound optionally substituted with one, two or three R ₁₄ groups. 4-, 5- or 6-membered cycloalkyl ring. In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 4-, 5- or 6-membered cycloalkyl ring .

In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ or -C(O)N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OH . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OR ₁₀ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OH. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein _R1 is halogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is C _1-6 alkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -CH ₃ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -CF ₃ .

In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OR ₁₀ . In some embodiments, is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein _R2 is halogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is C _1-6 alkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -CH ₃ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -CF ₃ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -OR ₁₀ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -OH.

In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl or C _1-6 haloalkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -CH ₃ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -CF ₃ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is halogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -OR ₁₀ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -OH. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -N(R ₁₀ )(R ₁₁ ).

In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OR ₁₀ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is halogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is C _1-6 alkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -CH ₃ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -CF ₃ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -OR ₁₀ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -OH.

In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen or C _1-6 alkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is C _1-6 alkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -CH ₃ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein _R5 is halogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -CF ₃ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -OR ₁₀ . In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -OH. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -N(R ₁₀ )(R ₁₁ ).

In some embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof: Formula (Ib); where: L is -C(R _9a )(R _9b )-, -C(O)- or -C(=N-OR ₁₆ )-; R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl Base, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O) OR ₁₀ 、-OC(O)N(R ₁₀ )(R ₁₁ )、-N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ )、-N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )( R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally replaced by one, Two or three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ); or R ₁ and R ₂ combine to form a 4-, 5-, or 6-membered cycloalkyl ring; a 4-, 5-, or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, where The 4-, 5- or 6-membered cycloalkyl ring; the 4-, 5- or 6-membered heterocycloalkyl ring; the 5- or 6-membered heteroaryl ring; or the benzene ring is optionally separated by one or two Or three R ₁₄ groups are substituted; or R ₂ and R ₃ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5-or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered hetero Aryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; or R ₃ and R ₄ combined to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or a 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered Heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or phenyl ring optionally substituted with one, two or three R ₁₄ groups; or R ₄ and R ₅ combined to form 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered ring Alkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; R ₆ for ; R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3- 6} cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally modified by one, two or three selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) group substitution; or R ₇ and R ₈ combined to form 4-, 5- or 6- 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring Ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; R _9a and R _9b is each independently selected from hydrogen, halogen, -OH, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy; each R ₁₀ is independently selected from hydrogen, C _1-6 alkyl base, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _{1 -9} heteroaryl, including C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _{C 2-9 heterocycloalkyl} , C _6-10 aryl The base and C _1-9 heteroaryl are optionally separated by one, two or three selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 Group substitution of cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl; each R ₁₁ is independently selected from hydrogen, C _1-6 alkyl and C _{1 -6} haloalkyl; each R ₁₂ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₃ is independently selected from C _1-6 alkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one or two Or three selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _{6- 10} aryl and C _1-9 heteroaryl groups are substituted; each R ₁₄ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N( R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ) , -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , - S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O )N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ ) (R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ ) via one, two or three (R ₁₁ ) is substituted with a group; each R ₁₅ is independently selected from halogen, side oxygen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ ) (R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N (R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , - C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O ) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N( R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _{1 -9} heteroaryl optionally contains one, two or three elements selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) is substituted with a group; R ₁₆ is selected from hydrogen and C _1-6 alkyl; and n is 0, 1, 2, 3 or 4.

In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R _9a )(R _9b )-. In some embodiments, is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R _9a )(R _9b )- and R _9a is selected from hydrogen, halogen, and C _{1 -6} alkyl. In some embodiments, is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R _9a )(R _9b )- and R _9b is selected from hydrogen, halogen and -OH . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is _-CH2- . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(OH)-. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(CH ₃ )-. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(OH)(CH ₃ )-.

In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(O)-.

In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR ₁₆ )-. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OH)-. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR ₁₆ )- and R ₁₆ is C _1-6 alkyl.

In some embodiments, is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

In some embodiments, it is a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 Heteroaryl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl is optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )( R ₁₁ ) is substituted with a group. In some embodiments, it is a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C _1-6 alkyl and C _{1- 6} haloalkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen and C _1-6 alkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are hydrogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are C _1-6 alkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are -CH ₃ . In some embodiments, is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is hydrogen and R ₈ is -CH ₃ . In some embodiments, is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is -CH ₃ and R ₈ is hydrogen.

In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a 4-, 5- or 6-membered cycloalkyl ring; 4- , 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5-or A 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, optionally substituted with one, two or three R ₁₄ groups. In some embodiments, is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of formula (Ib), optionally substituted with one, two or three R ₁₄ groups. benzene ring. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted benzene ring. In some embodiments, is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of formula (Ib), optionally substituted with one, two or three R ₁₄ groups. 5- or 6-membered heteroaryl ring. In some embodiments, is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 5- or 6-membered heteroaryl ring. In some embodiments, is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of formula (Ib), optionally substituted with one, two or three R ₁₄ groups. 4-, 5- or 6-membered heterocycloalkyl ring. In some embodiments, is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 4-, 5- or 6-membered heterocycloalkyl ring. In some embodiments, is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of formula (Ib), optionally substituted with one, two or three R ₁₄ groups. 4-, 5- or 6-membered cycloalkyl ring. In some embodiments, is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 4-, 5- or 6-membered cycloalkyl ring .

In some embodiments, it is a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ or -C(O)N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OH . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OR ₁₀ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OH. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein _R1 is halogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is C _1-6 alkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -CH ₃ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -CF ₃ .

In some embodiments, it is a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OR ₁₀ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is halogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is C _1-6 alkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -CH ₃ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -CF ₃ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -OR ₁₀ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -OH.

In some embodiments, it is a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl or C _1-6 haloalkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -CH ₃ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -CF ₃ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein _R3 is halogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -OR ₁₀ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -OH. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -N(R ₁₀ )(R ₁₁ ).

In some embodiments, it is a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OR ₁₀ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is halogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is C _1-6 alkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -CH ₃ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -CF ₃ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -OR ₁₀ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -OH.

In some embodiments, it is a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen or C _1-6 alkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is C _1-6 alkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -CH ₃ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein _R5 is halogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -CF ₃ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -OR ₁₀ . In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -OH. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -N(R ₁₀ )(R ₁₁ ).

In some embodiments, provided herein is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof: Formula (II); wherein: R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , - OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O )R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), - CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and - via one, two or three Substitution of N(R ₁₀ )(R ₁₁ ); or combination of R ₁ and R ₂ to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl Ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or a 6-membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; or R ₂ and R ₃ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5 - or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; or R ₃ and R ₄ combined to form 4 -, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- Or a 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring optionally via one, two or three R ₁₄ groups group substitution; or R ₄ and R ₅ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl group Ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene optionally substituted with one, two or three R ₁₄ groups; R ₆ is R _6a is selected from hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl, wherein C _1-6 alkyl and C _3-6 cycloalkyl are optionally separated by one, two or three R ₁₄ groups Substitution; or R _6a and R ₁₅ together form a bridge of -CH ₂ - or -CH ₂ CH ₂ -; R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 hetero Aryl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _{The 1-9} heteroaryl group is optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) group substitution; or R ₇ and R ₈ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6- Membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or the benzene ring is optionally substituted by one, two or three R ₁₄ groups; each R ₁₀ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one or two Or three selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _{6- 10} aryl and C _1-9 heteroaryl groups are substituted; each R ₁₁ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₂ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₃ is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 Cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one, two or three selected from halogen, C _1-6 alkyl, C ₁ -Substitution of _-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl groups; Each R ₁₄ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N (R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ) , -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N( R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N( R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one, two or Three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) are substituted; each R ₁₅ is independently selected from Halogen, side oxygen group, -CN, C _1-6 alkyl, C 1-6 haloalkyl, C _2-6 alkenyl, _{C 2-6 alkynyl, C 3-6 cycloalkyl ,} C _2-9 Heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC( O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C (O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ ) (R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ ) C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), among which C _1-6 alkyl and C _2-6 alkenyl , C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected by one, two or three Substituted from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ); or two R ₁₅ together form -CH ₂ - or - CH ₂ CH ₂ - bridge; and n is 0, 1, 2, 3 or 4.

In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is .

In some embodiments, is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is a C _1-6 alkane optionally substituted with one, two or three R ₁₄ groups base. In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is an unsubstituted C _1-6 alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is -CH ₃ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is -CH ₂ CH ₃ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is hydrogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

In some embodiments, is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R _is selected from . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is .

In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 Heteroaryl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl is optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )( R ₁₁ ) is substituted with a group. In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C _1-6 alkyl and C _{1- 6} haloalkyl. In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen and C _1-6 alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are hydrogen. In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are C _1-6 alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are -CH ₃ . In some embodiments, is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is hydrogen and R ₈ is -CH ₃ . In some embodiments, is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is -CH ₃ and R ₈ is hydrogen.

In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a 4-, 5- or 6-membered cycloalkyl ring; 4- , 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5-or A 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, optionally substituted with one, two or three R ₁₄ groups. In some embodiments, is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of formula (II), optionally substituted with one, two or three R ₁₄ groups. benzene ring. In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted benzene ring. In some embodiments, is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of formula (II), optionally substituted with one, two or three R ₁₄ groups. 5- or 6-membered heteroaryl ring. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 5- or 6-membered heteroaryl ring. In some embodiments, is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of formula (II), optionally substituted with one, two or three R ₁₄ groups. 4-, 5- or 6-membered heterocycloalkyl ring. In some embodiments, is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 4-, 5- or 6-membered heterocycloalkyl group ring. In some embodiments, is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of formula (II), optionally substituted with one, two or three R ₁₄ groups. 4-, 5- or 6-membered cycloalkyl ring. In some embodiments, is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 4-, 5- or 6-membered cycloalkyl ring .

In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ or -C(O)N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OH . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OR ₁₀ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OH. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein _R1 is halogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is C _1-6 alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -CH ₃ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -CF ₃ .

In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OR ₁₀ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is halogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is C _1-6 alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -CH ₃ . In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -CF ₃ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -OR ₁₀ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -OH.

In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl or C _1-6 haloalkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -CH ₃ . In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -CF ₃ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is halogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -OR ₁₀ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -OH. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -N(R ₁₀ )(R ₁₁ ).

In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OR ₁₀ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is halogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is C _1-6 alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -CH ₃ . In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -CF ₃ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -OR ₁₀ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -OH.

In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen or C _1-6 alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is C _1-6 alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -CH ₃ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is halogen. In some embodiments, it is a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -CF ₃ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -OR ₁₀ . In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -OH. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -N(R ₁₀ )(R ₁₁ ).

In some embodiments, provided herein is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof: Formula (III); wherein: R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , - OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O )R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), - CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and - via one, two or three Substitution of N(R ₁₀ )(R ₁₁ ); or combination of R ₁ and R ₂ to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl Ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or a 6-membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; or R ₂ and R ₃ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5 - or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; or R ₃ and R ₄ combined to form 4 -, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- Or a 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring optionally via one, two or three R ₁₄ groups group substitution; or R ₄ and R ₅ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl group Ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene optionally substituted with one, two or three R ₁₄ groups; R ₆ is or ; R _6a is selected from hydrogen and C _1-6 alkyl optionally substituted by one, two or three R ₁₄ groups; R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _{1- 6} alkyl, C _1-6 haloalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _{C 2-9 heterocycloalkyl} , C _6-10 aryl and C _1-9 heteroaryl, including C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, _{C 3-6 cycloalkyl, C 2-9 heterocycloalkyl ,} C _{6- 10} aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N( R ₁₀ ) (R ₁₁ ) is substituted with a group; or R ₇ and R ₈ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6 -membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; each R ₁₀ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, where C _1-6 Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl as appropriate With one, two or three selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl Substituted with groups of C _6-10 aryl and C _1-9 heteroaryl; each R ₁₁ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₂ is independently selected Selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₃ is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3- 6} cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally have one, two or three selected from halogen, C _1-6 Alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl Substituted with a group; each R ₁₄ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 Cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C( O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O) OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S( O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkane base, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl as appropriate. One, two or three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) are substituted; each R ₁₅ is independently selected from halogen, side oxygen group, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl , C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one or two One or three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ¹⁰ and -N(R ₁₀ )(R ₁₁ ) are substituted; and n is 0, 1, 2, 3 or 4.

In some embodiments, is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is a C _1-6 alkane optionally substituted with one, two or three R ₁₄ groups base. In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is an unsubstituted C _1-6 alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is -CH ₃ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is -CH ₂ CH ₃ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is hydrogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

In some embodiments, is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 Heteroaryl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl is optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )( R ₁₁ ) is substituted with a group. In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C _1-6 alkyl and C _{1- 6} haloalkyl. In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen and C _1-6 alkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are hydrogen. In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are C _1-6 alkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are -CH ₃ . In some embodiments, is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is hydrogen and R ₈ is -CH ₃ . In some embodiments, is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is -CH ₃ and R ₈ is hydrogen.

In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a 4-, 5- or 6-membered cycloalkyl ring; 4- , 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5-or A 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, optionally substituted with one, two or three R ₁₄ groups. In some embodiments, is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of formula (III), optionally substituted with one, two or three R ₁₄ groups. benzene ring. In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted benzene ring. In some embodiments, is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of formula (III), optionally substituted with one, two or three R ₁₄ groups. 5- or 6-membered heteroaryl ring. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 5- or 6-membered heteroaryl ring. In some embodiments, is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of formula (III), optionally substituted with one, two or three R ₁₄ groups. 4-, 5- or 6-membered heterocycloalkyl ring. In some embodiments, is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 4-, 5- or 6-membered heterocycloalkyl ring. In some embodiments, is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a compound of formula (III), optionally substituted with one, two or three R ₁₄ groups. 4-, 5- or 6-membered cycloalkyl ring. In some embodiments, is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted 4-, 5- or 6-membered cycloalkyl ring .

In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ or -C(O)N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OH . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OR ₁₀ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OH. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein _R1 is halogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is C _1-6 alkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -CH ₃ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -CF ₃ .

In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OR ₁₀ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is halogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is C _1-6 alkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -CH ₃ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -CF ₃ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -OR ₁₀ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is -OH.

In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl or C _1-6 haloalkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -CH ₃ . In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -CF ₃ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is halogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -OR ₁₀ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -OH. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is -N(R ₁₀ )(R ₁₁ ).

In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or -OR ₁₀ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is halogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is C _1-6 alkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -CH ₃ . In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -CF ₃ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -OR ₁₀ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is -OH.

In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen or C _1-6 alkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is C _1-6 alkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -CH ₃ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is halogen. In some embodiments, it is a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is C _1-6 haloalkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -CF ₃ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -OR ₁₀ . In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -OH. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is -N(R ₁₀ )(R ₁₁ ).

In some embodiments, provided herein is a compound selected from: or its pharmaceutically acceptable salt or solvate.

In some embodiments, provided herein is a compound that is: ; Or its pharmaceutically acceptable salt or solvate.

In some embodiments, provided herein is a compound selected from: or its pharmaceutically acceptable salt or solvate.

Any combination of the groups described above for the various variables is contemplated herein. Throughout this specification, groups and their substituents may be selected by those skilled in the art to provide stable moieties and compounds.

In some embodiments, the therapeutic agent(s) (e.g., compound of Formula (I'), (I), (Ia), (Ib), (II), or (III)) is present as a pharmaceutically acceptable salt in pharmaceutical compositions. In some embodiments, any of the compounds described above are suitable for use in any of the methods or compositions described herein. Additional forms of isomers of the compounds disclosed herein

Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, compounds described herein have one or more double bonds. Compounds presented herein include all cis, trans, homo, retro, iso ( E ) and iso ( Z ) isomers and corresponding mixtures thereof. In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some cases, compounds described herein have one or more chiral centers and each center exists in the R configuration or the S configuration. The compounds described herein include all diastereomeric, enantiomeric and epimeric forms as well as corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers resulting from a single preparation step, combination, or interconversion can be used in the applications described herein. . In some embodiments, compounds described herein are prepared as optically pure enantiomers by chiral chromatography of racemic mixtures. In some embodiments, the compounds described herein are in their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds, and these non-diastereomeric compounds are separated. enantiomers, and are prepared by recovering optically pure enantiomers. In some embodiments, dissociable complexes are preferred (eg, crystalline diastereomeric salts). In some embodiments, diastereomers have different physical properties (eg, melting point, boiling point, solubility, reactivity, etc.) and are separated by exploiting these differences. In some embodiments, diastereomers are separated based on solubility differences by chiral chromatography or, preferably, by separation/resolution techniques. In some embodiments, the optically pure enantiomer is then recovered along with the resolving agent by any practical method that does not result in racemization. labeled compounds

In some embodiments, the compounds described herein are in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds in the form of pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those detailed herein, but in which one or more atoms have an atomic mass or masses different from those typically seen in nature. Atomic substitution of atomic mass or mass number of a number. Examples of isotopes incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H, ³ H ^{, 13 C, 14 C} , ¹⁵ N, ^{17 each} O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds described herein containing the above isotopes and/or other isotopes of other atoms and their pharmaceutically acceptable salts, esters, solvates, hydrates or derivatives are within the scope of the present invention. Certain isotopically labeled compounds, such as those incorporating radioactive isotopes such as ³ H and ¹⁴ C, can be used in drug and/or substrate tissue distribution analysis. Tritiated (ie, ³ H) and carbon-14 (ie, ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Additionally, substitution with heavy isotopes (such as deuterium, ie, ² H) results in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, isotopically labeled compounds, pharmaceutically acceptable salts, esters, solvates, hydrates or derivatives thereof are prepared by any suitable method.

In some embodiments, compounds described herein are labeled by other methods, including, but not limited to, using chromophores or fluorescent moieties, bioluminescent markers, or chemiluminescent markers. Medically acceptable salt

In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts in the form of pharmaceutical compositions.

In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting the purified compound in its free form with a suitable acid or base, and isolating the compound thus formed. salt to prepare. Solvates

In some embodiments, compounds described herein exist as solvates. In some embodiments, are methods of treating disease by administering these solvates. Further described herein are methods of treating disease by administering such solvates in pharmaceutical compositions.

Solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture using an organic solvent, including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein. synthetic compounds

In some embodiments, the compounds described herein are synthesized using methods described in the chemical literature, using methods described herein, or by combinations thereof. In addition, solvents, temperatures, and other reaction conditions presented herein may vary.

In other embodiments, starting materials and reagents for the synthesis of compounds described herein are synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

In additional embodiments, the compounds described herein and other related compounds having different substituents are prepared using techniques and materials described herein and identified in the art, such as described in, e.g., Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1 to 17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1 to 5 and supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1 to 40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry, 4th Edition (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry, 4th Edition, Volumes A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis, 3rd ed. (Wiley 1999) (the entirety of which is incorporated by reference for the purposes of this disclosure). General methods for preparing compounds as disclosed herein can be derived from reactions and these reactions can be modified by using appropriate reagents and conditions for the introduction of the various moieties found in the formulas as provided herein. As a guide, the following synthetic methods can be utilized. Use protecting groups

In the reaction, protection of reactive functional groups (e.g., hydroxyl, amine, imine, thio, or carboxyl) may be necessary, where this is required in the final product, to avoid their undesired participation in the reaction. . Protecting groups are used to block some or all of the reactive moieties and prevent these groups from participating in chemical reactions until the protecting group is removed. Preferably, each protecting group can be removed by different methods. Protective groups cleaved under completely different reaction conditions meet different removal requirements.

Protecting groups can be removed by acids, bases, reducing conditions (such as, for example, hydrogenolysis), and/or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetal, and tert-butyldimethylsilyl are acid labile and can be used in the presence of Cbz groups (which can be converted by hydrogen The carboxyl and hydroxyl reactive moieties are protected under the amine group protected by the Fmoc group (which is base-labile). The carboxylic acid and hydroxyl reactive moieties can be removed by a base in the presence of an amine blocked by an acid-labile group such as tert-butyl carbamate or a carbamate that is both acid- and base-stable but hydrolytically removable. Stabilizing groups such as, but not limited to, methyl, ethyl and acetyl block.

Carboxylic acid and hydroxyl reactive moieties can also be blocked by hydrolytically removable protecting groups such as benzyl groups, while amine groups capable of hydrogen bonding with acids can be blocked by base-labile groups such as Fmoc. The carboxylic acid reactive moiety can be protected by conversion to a simple ester compound as exemplified herein, which includes conversion to an alkyl ester, or it can be protected by an oxidatively removable protecting group such as 2,4-dimethoxy benzyl), while coexisting amine groups can be blocked by fluoride-labile silicon carbamates.

Allyl blocking groups are useful in the presence of acid and base protecting groups, as the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, allyl-blocked carboxylic acids can be deprotected using a ^Pd0 -catalyzed reaction in the presence of an acid-labile tert-butylcarbamate or a base-labile acetate amine protecting group. Another form of protecting group is a resin to which compounds or intermediates can be attached. As long as the residue is attached to the resin, the functional groups are blocked and unreactive. Once released from the resin, the functional groups are available for reaction.

Typical blocking/protecting groups can be selected from:

A detailed description of other protecting groups plus techniques suitable for their creation and removal is described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, the disclosure of which is incorporated herein by reference. Treatment and prevention methods

In some embodiments, a method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) ) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) ) or (III) a compound or a pharmaceutically acceptable salt or solvate thereof, wherein the metabolic disease is selected from the group consisting of type 2 diabetes, atherosclerosis, obesity and gout. In some embodiments, a method of treating type 2 diabetes in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), ( II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating atherosclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating obesity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating gout in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, a method of treating liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) a compound or a pharmaceutically acceptable salt or solvate thereof, wherein the liver disease is selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH) , viral hepatitis and cirrhosis.

In some embodiments, a method of treating lung disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) a compound or a pharmaceutically acceptable salt or solvate thereof, wherein the lung disease is selected from the group consisting of asthma, COPD and idiopathic pulmonary fibrosis.

In some embodiments, a method of treating a central nervous system disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof, wherein the central nervous system disease is selected from Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, traumatic brain injury, ischemic stroke and reperfusion, hemorrhagic stroke, epilepsy and depression. In some embodiments, a method of treating Alzheimer's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib ), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating multiple sclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating amyotrophic lateral sclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating multiple sclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating Parkinson's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating Huntington's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), ( II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating traumatic brain injury in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating ischemic stroke and reperfusion in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), ( Compound Ib), (II) or (III) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating stroke in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating epilepsy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating depression in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) ) or (III) compound or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, a method of treating a neurodegenerative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is rheumatoid arthritis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is multiple sclerosis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is psoriasis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is lupus. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is inflammatory bowel disease. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is Crohn's disease. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is ulcerative colitis.

In some embodiments, a method of treating cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), ( II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), ( II) or (III) a compound or a pharmaceutically acceptable salt or solvate thereof, wherein the cardiovascular disease is atherosclerosis or stroke. In some embodiments, a method of treating atherosclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating stroke in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Formula (I'), (I), (Ia), (Ib), (II) or (III) compound or a pharmaceutically acceptable salt or solvate thereof. Pharmaceutical compositions and administration methods

The NLRP3 inhibitors described herein are administered to an individual in a biocompatible form suitable for administration to treat or prevent a disease, disorder or condition. Administration of an NLRP3 inhibitor as described herein can be in any pharmacological form, including a therapeutically effective amount of the NLRP3 inhibitor alone or in combination with a pharmaceutically acceptable carrier.

In certain embodiments, the compounds described herein are administered as pure chemicals. In other embodiments, the compounds described herein are formulated based on the chosen route of administration and as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed., Mack Pub. Co., Easton, PA (2005) ), a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient or a physiologically suitable excipient) selected in accordance with standard pharmaceutical practice (or acceptable) carrier) combination.

Accordingly, provided herein are pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if the carrier(s) are compatible with the other ingredients of the composition and not deleterious to the recipient (ie, the individual) of the composition.

In some embodiments, it is a pharmaceutical composition, which includes a pharmaceutically acceptable carrier and a compound of formula (I'), (I), (Ia), (Ib), (II) or (III) or a pharmaceutical thereof. Acceptable salts or solvates above. In some embodiments, it is a pharmaceutical composition, which includes a pharmaceutically acceptable carrier and a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, it is a pharmaceutical composition, which includes a pharmaceutically acceptable carrier and a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, it is a pharmaceutical composition, which includes a pharmaceutically acceptable carrier and a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof.

Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (I'), (I), (Ia), (Ib), (II) or (III) or a pharmaceutical thereof. Acceptable salts or solvates above. In some embodiments, it is a pharmaceutical composition, which consists essentially of a pharmaceutically acceptable carrier and a compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, it is a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, it is a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, it is a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, it is a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, it is a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof.

In certain embodiments, compounds as described herein are substantially pure because they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as, for example, in synthetic method steps. Contaminating intermediates or by-products created in one or more of the

Such formulations include those suitable for oral, topical, buccal, parenteral (eg, subcutaneous, intramuscular, intradermal, or intravenous) or aerosol administration.

Exemplary pharmaceutical compositions are used in the form of pharmaceutical preparations, e.g., in solid, semi-solid, or liquid forms, containing one or more of the disclosed compounds as active ingredients and suitable for topical, enteral, or parenteral use. in a mixture of organic or inorganic carriers or excipients. In some embodiments, the active ingredients are, for example, mixed with commonly used non-toxic pharmaceutically acceptable carriers in tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

In some embodiments, an NLRP3 inhibitor described herein is administered to an individual in a biocompatible form suitable for topical administration to treat or prevent unwanted diseases, disorders, or conditions. "A biocompatible form suitable for topical administration" means a form of the NLRP3 inhibitor to be administered in which the therapeutic effects of the inhibitor outweigh any toxic effects. Administration of an NLRP3 inhibitor as described herein can be in any pharmacological form, including a therapeutically effective amount of the NLRP3 inhibitor alone or in combination with a pharmaceutically acceptable carrier.

Topical administration of NLRP3 inhibitors can be in the form of aerosols, semi-solid pharmaceutical compositions, powders or solutions. The term "semi-solid composition" means an ointment, cream, salves, jelly, or other pharmaceutical composition of substantially similar consistency suitable for application to the skin. Examples of semisolid compositions are disclosed in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lachman, Lieberman and Kanig (1970) by Lea and Febiger and Remington's Pharmaceutical Sciences, 15th Edition (1975), published by Mack Publishing Company. provided in Chapter 67.

Dermal or skin patches are another method for transdermal delivery of therapeutic agents or pharmaceutical compositions described herein. The patch may provide an absorption enhancer (such as DMSO) to increase absorption of the compound. Patches may include those that control the rate of drug delivery to the skin. Patches are available in a variety of drug delivery systems, each including a library system or a single-chip system. The reservoir design may, for example, have four layers: an adhesive layer that directly contacts the skin, a control membrane that controls the diffusion of drug molecules, a reservoir for the drug molecules, and a waterproof backing. This design delivers a uniform amount of drug over a specific period of time, and the delivery rate must be less than the saturation limits of different skin types. Monolithic designs (for example) typically have only three layers: an adhesive layer, a polymer matrix containing the compound, and a waterproof backing. This design brings a saturated amount of medicine into the skin. Therefore, delivery is controlled through the skin. Because the amount of drug in the patch is reduced below saturation, the delivery rate decreases.

In one embodiment, the topical composition may, for example, be in the form of a hydrogel based on polyacrylic acid or polyacrylamide; in an ointment, for example using polyethylene glycol (PEG) as a carrier, such as the standard ointment DAB 8 (50% PEG 300, 50% PEG 1500); or in the form of emulsions, especially microemulsions based on water-in-oil or oil-in-water, optionally with added liposomes. Suitable penetration accelerators (entrainers) include serotonin derivatives such as dimethylsulphite (DMSO) or decylmethylsulphite (decyl-MSO) and transcutol (diethylene glycol monoethyl ether) or cyclodextrin; and pyrrolidinones, such as 2-pyrrolidinone, N-methyl-2-pyrrolidinone, 2-pyrrolidinone-5-carboxylic acid or biodegradable N-(2-hydroxyethyl)-2-pyrrolidine Ketones and their fatty acid esters; urea derivatives, such as dodecyl urea, 1,3-dodecyl urea and 1,3-diphenyl urea; and terpenes, such as D-limonene, menthone , a-terpineol, carvone, limonene oxide or 1,8-eucalyptol.

Ointments, pastes, creams and gels may also contain excipients such as starch, tragacanth, cellulose derivatives, polyethylene glycols, polysiloxanes, bentonite, silicic acid and talc, or mixtures thereof. Powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. The solution of nanocrystalline antimicrobial metal can be converted into an aerosol or spray by any of the known methods conventionally used to prepare aerosol pharmaceutical agents. Generally, these methods involve pressurizing or providing a means to pressurize a container of solution, usually using an inert carrier gas, and passing the pressurized gas through small holes. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

The carrier may also contain other pharmaceutically acceptable excipients used to modify or maintain the pH, osmolarity, viscosity, transparency, color, sterility, stability, dissolution rate, or odor of the formulation. Anti-skin aging compositions may further include antioxidants, sunscreens, natural retinoids (eg, retinol), and other additives commonly found in skin treatment compositions.

In some embodiments of preparing solid compositions such as tablets, the main active ingredient is combined with a pharmaceutical carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, Magnesium stearate, dicalcium phosphate or gum) and other pharmaceutical diluents (e.g., water) are mixed to form a solid preformulated composition containing a homogeneous mixture of the disclosed compound or a nontoxic pharmaceutically acceptable salt thereof. When such preformulated compositions are referred to as homogeneous, it is meant that the active ingredients are uniformly dispersed throughout the composition such that the composition can be readily subdivided into equivalent unit dosage forms, such as tablets, pills, and capsules.

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, and the like), the subject composition is combined with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate) and/or mixed with any of the following: (1) fillers or extenders, such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, hydroxypropylmethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic; (3) ) Humectants, such as glycerol; (4) Disintegrants, such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain Silicates and sodium carbonate; (5) solution retardants, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds, (7) wetting agents, such as, for example, docusate sodium, cetyl alcohol and mono Glyceryl stearate; (8) adsorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof ; and (10) colorants. In some embodiments, in the case of capsules, tablets, and pills, the compositions include buffering agents. In some embodiments, similar types of solid compositions are also employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose and high molecular weight polyethylene glycols and the like.

In some embodiments, tablets are prepared by compression or molding, optionally with one or more accessory ingredients. In some embodiments, the compressed tablets are prepared using a binder (eg, gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (eg, sodium starch glycolate or cross-linking Sodium carboxymethylcellulose), surfactant or dispersant. In some embodiments, molded tablets are prepared by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. In some embodiments, tablets and other solid dosage forms (such as dragees, capsules, pills, and granules) are scored or prepared with coatings and shells (such as enteric coatings and other coatings).

Compositions for inhalation or insufflation include solutions and suspensions, and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In some embodiments, in addition to the subject composition, the liquid dosage form contains an inert diluent such as, for example, water or other solvents, solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl Alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oil (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofuranol, polyethylene Fatty acid esters of glycols and sorbitan, cyclodextrins and their mixtures.

In some embodiments, in addition to the subject composition, the suspension contains suspending agents, such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, metahydroxide Aluminum, bentonite, agar and tragacanth and mixtures thereof.

In some embodiments, powders and sprays contain excipients, in addition to the subject composition, such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. In some embodiments, the spray additionally contains conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

The compositions and compounds disclosed herein may be administered via aerosol. This is accomplished by preparing aqueous aerosols, liposome formulations or solid particles containing the compound. In some embodiments, non-aqueous (eg, fluorocarbon propellant) suspensions are used. In some embodiments, a sonic nebulizer is used because it minimizes exposure of the agent to shear that results in degradation of compounds contained in the subject composition. Generally, aqueous aerosols are prepared by formulating an aqueous solution or suspension of a standard composition together with conventional pharmaceutically acceptable carriers and stabilizers. Such carriers and stabilizers vary with the requirements of the specific target composition, but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), harmless proteins (such as serum Albumin), sorbitan esters, oleic acid, lecithin, amino acids (such as glycine), buffers, salts, sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

Pharmaceutical compositions suitable for parenteral administration include the subject composition in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders which are used Prior to reconstitution in a sterile injectable solution or dispersion, in some embodiments, the sterile injectable solution or dispersion contains antioxidants, buffers, bacteriostatic agents, such that the formulation is isotonic with the blood of the intended recipient. Solute or suspending agent or thickening agent.

Examples of suitable aqueous and non-aqueous carriers that may be employed in pharmaceutical compositions include water, ethanol, polyols (such as glycerin, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils (such as olive oil) and Injectable organic esters (such as ethyl oleate) and cyclodextrins. Proper flowability is maintained, for example in the case of dispersions, by the use of coating materials such as lecithin, by maintaining the required particle size and by the use of surfactants.

The dosage of a composition comprising at least one compound described herein varies depending on the condition of the patient (eg, human), ie, the stage of the disease, general health, age, and other factors.

The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dosage and appropriate duration and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the particular form of the active ingredient and the method of administration. Generally speaking, appropriate doses and treatment regimens provide sufficient to provide therapeutic and/or preventive benefit (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or symptom severity reduce the amount of the composition(s). Optimal doses are generally determined using experimental models and/or clinical trials. In some embodiments, the optimal dose depends on the patient's body mass, body weight, or blood volume.

Oral dosages generally range from about 1.0 mg to about 1000 mg one to four times or more per day.

Dosage administration may depend upon the pharmacokinetic parameters of the dosage formulation and the route of administration employed.

It is especially advantageous to formulate the compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suitable as unitary dosages for the mammalian subject to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage form strengths are specified by and depend directly upon: (a) the unique characteristics of the NLRP3 inhibitor and the specific therapeutic effect to be achieved and (b) the correlation of the active compounds when compounded for therapeutic susceptibility in an individual The inherent limits of craft. Specific dosages are readily calculated by those skilled in the art, for example, based on the patient's approximate weight or body surface area or volume of body space that would be occupied. Dosage will also be calculated depending on the specific route of administration chosen. The calculations required to determine the appropriate dosage for treatment can be further calculated on a routine basis by those skilled in the art. These calculations can be performed by one skilled in the art without undue experimentation based on the NLRP3 inhibitor activity disclosed herein in the assay preparation of target cells. Precise dosages are determined in conjunction with standard dose-response studies. It is understood that the actual amount of the composition to be administered will be determined by the operator based on relevant circumstances, including the condition to be treated, the selection of the composition to be administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the chosen investment channel.

The toxicity and therapeutic efficacy of these NLRP3 inhibitors can be determined by standard pharmaceutical procedures in cell cultures or experimental animals (e.g., for determination of LD ₅₀ (dose lethal to 50% of the population) and ED ₅₀ (treatment effective in 50% of the population) dose)) determination. The dose ratio between toxic and therapeutic effects is the therapeutic index, expressed as the ratio LD ₅₀ /ED ₅₀ . NLRP3 inhibitors with a large therapeutic index are preferred. Although NLRP3 inhibitors with toxic side effects can be used, delivery systems that target these inhibitors to infected tissue sites should be carefully designed to minimize potential damage to uninfected cells and thereby reduce side effects.

Data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The doses of such NLRP3 inhibitors are preferably within a range of circulating concentrations that include _ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. For any NLRP3 inhibitor used in the methods described herein, the therapeutically effective dose can first be assessed from cell culture assays. Doses can be formulated in animal models to achieve a range of circulating plasma concentrations that include the _IC50 (i.e., the concentration of the NLRP3 inhibitor that achieves half-maximal inhibition of symptoms) as determined in cell culture. This information can be used to more precisely determine useful doses in humans. The levels in plasma can be measured, for example, by high performance liquid chromatography. Example

The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein. These examples, and all document citations throughout this specification, are incorporated by reference for all legal purposes served thereby. Starting materials and reagents used to synthesize the compounds described herein may be synthesized or may be obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

Standard abbreviations and acronyms are used herein as defined in J. Org. Chem. 2007 72(1): 23A-24A. Other abbreviations and acronyms used in this article are as follows: THF Tetrahydrofuran ACN Acetonitrile DMF N,N-dimethylformamide tOH ethanol OH Methanol DCM Dichloromethane tOc Ethyl acetate HATU O-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate DIEA N,N-diisopropylethylamine P ₂ O ₅ Phosphorus pentoxide mOH methanesulfonic acid NaH sodium hydride Mg magnesium LiAlH ₄ Lithium aluminum hydride PPH ₃ Triphenylphosphine DIAD Diisopropyl azodicarboxylate SO ₃ .DMF N,N-dimethylformamide sulfur trioxide complex SOCl ₂ Thionyl chloride NH ₄ OH Ammonium hydroxide t-BuONa Sodium tert-butoxide NaOH sodium hydroxide Mw microwave OVN Stay overnight rt room temperature SM starting material Example 1 : Synthesis of 2-(6-( hydroxy (1- methylpiperidin -3- yl ) methyl )-4,5- dimethylpyridazin -3- yl )-5-( trifluoromethyl ) Phenol ( compound 1)

Step 1: To a solution of 3,6-dichloro-4,5-dimethylpyridazine (3.54 g, 20 mmol) in THF (150 mL) was added pyridin-3-yl-acetonitrile (2.5 g , 21 mmol). The solution was degassed, backfilled with _N2 and cooled to 0 °C. Add NaHMDS (2N, 21 mL in THF, 42 mmol). The reaction mixture was warmed to room temperature for 2 hours. The reaction mixture was stirred vigorously open to air for 5 hours. The reaction was quenched with saturated _NaHCO3 and diluted with EtOAc. The organic phase was separated and the aqueous phase was extracted with EtOAc. _The combined organic layers were washed with brine, dried over _Na2SO4 , filtered and concentrated. The residue was triturated with hexane/EtOAc to give (6-chloro-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (3 g).

Step ₂ : Combine (6-chloro-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (300 mg, 1.0 eq), (2-hydroxy- 4-(Trifluoromethyl)phenyl)boronic acid (350 mg, 1.3 eq), PdCl ₂ (dppf) (80 mg, 10%) and Na ₂ CO ₃ (290 mg, 2.0 eq) in 2 Combine with oxane (20 mL) and water (5 mL). The resulting mixture was heated at 100°C for 8 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water, brine and concentrated in vacuo. The residue was purified by silica gel chromatography to obtain (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(pyridine-3 -Methyl ketone (205 mg).

Step 3: (6-(2-Hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (200 mg , 1.0 eq) was dissolved in MeOH (10 mL) and THF (10 mL) and the solution was cooled to 0 °C. Add _NaBH4 (11 mg, 0.5 eq) at 0°C. The resulting mixture was stirred at 0°C for 15 minutes. The reaction was quenched with saturated _NaHCO3 . The mixture was extracted with EtOAc and the EtOAc solution was concentrated in vacuo to give 2-(6-(hydroxy(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5- (Trifluoromethyl)phenol (201 mg) was used without further purification.

Step 4: To 2-(6-(hydroxy(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl in MeOH (100 mL) and water (1 mL) To a solution of )-5-(trifluoromethyl)phenol (200 mg, 1.0 eq) was added PtO ₂ (98 mg, 0.8 eq). The mixture was degassed by bubbling _N2 gas for 20 minutes and then hydrogenated under _H2 (balloon) at room temperature for 15 hours. The catalyst was removed by filtration and the solvent was concentrated in vacuo to give 2-(6-(hydroxy(piperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)- 5-(Trifluoromethyl)phenol (185 mg) was used without purification.

Step 5: Combine 2-(6-(hydroxy(piperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (185 mg , 1.0 eq) was dissolved in 1,2-dichloroethane (20 mL) and HCHO (48 mg, 37% in water, 1.2 eq) and 2 drops of AcOH were added. The mixture was stirred at room temperature for 30 min and NaBH(AcO) ₃ (165 mg, 1.5 eq) was added. The resulting mixture was stirred at room temperature for 30 minutes and quenched with saturated _NaHCO3 and stirred at room temperature for 10 minutes. The mixture was extracted with DCM (4 x 25 mL) and the combined DCM extracts were concentrated in vacuo. The residue was purified by silica gel chromatography to obtain 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)-4,5-dimethylpyridazine-3 as a white solid -yl)-5-(trifluoromethyl)phenol ( compound 1 ) (48 mg). ESI-MS (EI ⁺ , m/z): 396.1.

Stereoisomer 1A (a mixture of two compounds) and Stereoisomer 1B (a mixture of two compounds) were separated from compound 1 by C18 preparative HPLC. Peak 1 is stereoisomer 1A , and peak 2 is stereoisomer 1B . Stereoisomer 1A ESI-MS (EI ⁺ , m/z): 396.2. Stereoisomer 1B ESI-MS (EI ⁺ , m/z): 396.2. Example 2 : Synthesis of (6-(2- hydroxy -4-( trifluoromethyl ) phenyl )-4,5- dimethylpyridazin -3- yl )(1- methylpiperidin -3- yl ) Methyl ketone ( compound 2)

Step ₁ : Combine (6-chloro-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (300 mg, 1.0 eq), (2-methoxy 4-(trifluoromethyl)phenyl)boronic acid (360 mg, 1.3 eq), PdCl ₂ (dppf) (82 mg, 10%), and Na ₂ CO ₃ (300 mg, 2.0 eq) in dioxane (20 mL) and water (5 mL) were combined. The resulting mixture was heated at 100°C for 8 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water, brine and concentrated in vacuo. The residue was purified on a silica gel column to obtain (6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(pyridin- 3-yl)methanone (262 mg).

Step 2: Add (6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone ( 260 mg, 1.0 eq) was dissolved in MeOH (20 mL) and THF (20 mL). At 0 °C, NaBH ₄ (13 mg, 0.5 eq) was added to the solution. The resulting mixture was stirred at 0°C for 30 min and quenched with saturated _NaHCO3 . The mixture was extracted with EtOAc and the EtOAc solution was concentrated in vacuo to give (6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl )(pyridin-3-yl)methanol (259 mg), which was used without further purification.

Step 3: To (6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazine in MeOH (100 mL) and water (1 mL) To a solution of -3-yl)(pyridin-3-yl)methanol (250 mg, 1.0 eq) were added PtO ₂ (117 mg, 0.8 eq) and (Boc) ₂ O (168 mg, 1.2 eq). The mixture was degassed with bubbling _N2 gas for 20 minutes and then hydrogenated under _H2 (balloon) at room temperature for 1.5 hours. The _H2 balloon was then removed and the mixture was stirred at room temperature overnight. The catalyst was removed by filtration and the solvent was concentrated in vacuo. The residue was purified on a silica column to obtain 3-(hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl))-4,5-dimethylpyridazin-3-yl )Methyl)piperidine-1-carboxylic acid tert-butyl ester (264 mg).

Step 4: Add 3-(hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl))-4,5-dimethyl in anhydrous DCM (25 mL) at 0 °C. To a solution of tert-butylpyridazin-3-ylmethyl)piperidine-1-carboxylate (260 mg, 1.0 eq) was added DMP (268 mg, 1.2 eq) and stirred at 0°C for 1 hour. Additional DMP (30 mg) was added and the reaction was stirred at room temperature for 30 min and then quenched with saturated NaHCO ₃ . The mixture was concentrated and the residue was purified on a silica column to obtain 3-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazine-3 -Carbonyl)piperidine-1-carboxylic acid tert-butyl ester (198 mg).

Step 5: Add 3-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5 in anhydrous DCM (20 mL) at ₀ °C under N To a solution of -dimethylpyridazine-3-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (190 mg, 1.0 eq) was added BBr ₃ (5 eq). The mixture was stirred at 0°C for 1 hour and then at room temperature for 6 hours. The reaction was quenched with 0°C water and stirred at room temperature for 30 minutes. Add _saturated NaHCO to adjust pH to approximately 10. The mixture was extracted with DCM (3 x 50 mL). The combined extracts were concentrated in vacuo to give (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(piperidine-3 -Methyl ketone (97 mg).

Step 6: Under the reaction conditions described in Example 1, Step 5, from (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazine-3- yl)(piperidin-3-yl)methanone (56 mg) to obtain (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyrazin-3-yl )(1-methylpiperidin-3-yl)methanone (28 mg) ( Compound 2 ). ESI-MS (EI ⁺ , m/z): 394.2. Example 3 : Synthesis of 2-(6-(1- hydroxy- 1-(1- methylpiperidin -3- yl ) ethyl )-4,5- dimethylpyridin -3- yl )-5-( Trifluoromethyl ) phenol ( compound 3)

Compound 2 (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(1- A solution of methylpiperidin-3-yl)methanone (15 mg) was treated with MeMgBr (2N, 76 μl, 4.0 eq). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated _NH4Cl and extracted with DCM (3 x 20 mL). The combined extracts were concentrated in vacuo and the residue was purified on HPLC to give 2-(6-(1-hydroxy-1-(1-methylpiperidin-3-yl)ethyl)-4,5 -Dimethylpyrazin-3-yl)-5-(trifluoromethyl)phenol (8 mg) ( Compound 3 ). ESI-MS (EI ⁺ , m/z): 410.2. Example 4 : Synthesis of 2-(6-( fluoro ( pyridin -3- yl ) methyl )-4,5- dimethylpyridazin -3- yl )-5-( trifluoromethyl ) phenol ( compound 4)

Step 1: Dissolve (6-chloro-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (1.0 g, 1.0 eq) in MeOH (20 mL) and THF (20 mL) and cool to 0°C. At 0 °C, NaBH ₄ (80 mg, 0.5 eq) was added. The resulting mixture was stirred at 0°C for 15 minutes. The reaction was quenched with saturated _NaHCO3 . The mixture was extracted with EtOAc and the EtOAc solution was concentrated in vacuo to give (6-chloro-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanol (0.95 g) without further purification You can use it.

Step 2: To (6-chloro-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanol (300 mg, 1.0) in anhydrous DCM (10 mL) at 0 °C eq), DAST (388 mg, 2.0 eq) was added. The mixture was stirred at room temperature overnight. Additional DAST (100 mg) was added and the reaction was stirred at room temperature for an additional 5 hours. The reaction was quenched with saturated _NaHCO3 at 0 °C, and the aqueous phase was extracted with DCM (2 x 20 mL). The combined extracts were concentrated in vacuo and the residue was purified on a silica column to give 3-chloro-6-(fluoro(pyridin-3-yl)methyl)-4,5-dimethylpyridazine ( 174 mg).

Step ₃ : Add 3-chloro-6-(fluoro(pyridin-3-yl)methyl)-4,5-dimethylpyridazine (150 mg, 1.0 eq), (2-hydroxy- 4-(Trifluoromethyl)phenyl)boronic acid (160 mg, 1.3 eq), PdCl ₂ (dppf) (40 mg, 10%) and Na ₂ CO ₃ (130 mg, 2.0 eq) in dioxane (10 mL) and water (3 mL). The resulting mixture was heated at 100°C for 8 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water, brine and concentrated in vacuo. The residue was purified on a silica gel column to obtain ZMG-3134 2-(6-(fluoro(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-( Trifluoromethyl)phenol (143 mg).

Step 4: Add 3-(hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl))-4,5-dimethyl in anhydrous DCM (25 mL) at 0 °C. To a solution of tert-butylpyridazin-3-ylmethyl)piperidine-1-carboxylate (260 mg, 1.0 eq) was added DMP (268 mg, 1.2 eq) and stirred at 0°C for 1 hour. Additional DMP (30 mg) was added and the reaction was stirred at room temperature for 30 min and then quenched with saturated NaHCO ₃ . The mixture was concentrated and the residue was purified on a silica column to obtain 3-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazine-3 -Carbonyl)piperidine-1-carboxylic acid tert-butyl ester ( compound 4 ) (198 mg). ESI-MS (EI ⁺ , m/z): 378.3. Example 5 : Synthesis of 2-(4,5- dimethyl- 6-((1- methylpiperidin -3- yl ) methyl ) pyridazin -3- yl )-5-( trifluoromethyl ) phenol ( Compound 5)

Step 1: To a solution of compound 4 (120 mg) in MeOH (40 mL) was added _PtO2 (40 mg) and degassed under vacuum, then hydrogenated under a _H2 balloon for 15 h. The catalyst was removed through a pad of celite and the reaction mixture was concentrated in vacuo to give 2-(4,5-dimethyl-6-(piperidin-3-ylmethyl)pyridazin-3-yl) -5-(Trifluoromethyl)phenol (92 mg).

Step 2: Under the reaction conditions described in Example 1, Step 5, from 2-(4,5-dimethyl-6-(piperidin-3-ylmethyl)pyridazin-3-yl)-5 -(Trifluoromethyl)phenol (92 mg) gave 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)- 5-(Trifluoromethyl)phenol (21 mg) ( Compound 5 ). ESI-MS (EI ⁺ , m/z): 380.3. Example 6 : Synthesis of 2-(6-( methoxy (1- methylpiperidin -3- yl ) methyl )-4,5- dimethylpyridazin -3- yl )-5-( trifluoromethyl base ) phenol ( compound 6)

Step 1: To 2-(6-(fluoro(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-( To a solution of trifluoromethyl)phenol (100 mg) was added 2 M NaOMe in MeOH (2 mL). The resulting mixture was heated in a sealed tube at 90°C overnight. The mixture was cooled and diluted with water (40 mL) and extracted with ethyl acetate (3 x 40 mL). The combined extracts were concentrated in vacuo. The residue was purified on a silica column to obtain 2-(6-(methoxy(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(tris Fluoromethyl)phenol (81 mg).

Step 2: To 2-(6-(methoxy(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (60 mg), PtO2 (25 mg) was added and degassed under vacuum and hydrogenated under a H ₂ balloon for 15 hours to obtain 2-(6-(methoxy(piperidin-3-yl)methyl)-4 ,5-Dimethylpyrazin-3-yl)-5-(trifluoromethyl)phenol (42 mg).

Step 3: Under the reaction conditions described in Example 1, Step 5, from 2-(6-(methoxy(piperidin-3-yl)methyl)-4,5-dimethylpyridazine-3 -yl)-5-(trifluoromethyl)phenol (42 mg) gave 2-(6-(methoxy(1-methylpiperidin-3-yl)methyl)-4,5-dimethyl Pyrazin-3-yl)-5-(trifluoromethyl)phenol (5 mg) ( Compound 6 ). ESI-MS (EI ⁺ , m/z): 410.2. Example 7 : Synthesis of 3- fluoro -5- methyl -2-(6-((1- methylpiperidin -3- yl ) methyl ) pyrazin -3- yl ) phenol ( Compound 7)

Step 1: To 3-methylenepiperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.0 eq) was added 9-BBN (0.5 M, 5.1 mL, 1.0 eq) at ₀ °C under N . The mixture was stirred at room temperature for 10 minutes and then in a sealed tube at 70°C for 1 hour. The mixture was cooled and the solvent was removed in vacuo to give tert-butyl 3-((9-borobicyclo[3.3.1]non-9-yl)methyl)piperidine-1-carboxylate without further purification. can use it.

Step 2: Combine 3-((9-borobicyclo[3.3.1]nonan-9-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 1.0 eq), 3,6-di Bromopyridazine (300 mg, 2.0 eq), PdCl ₂ (dppf) (40 mg, 0.1eq) and Na ₂ CO ₃ (135 mg, 2.0 eq) in dioxane (15 mL) and water (5 mL) merge. The mixture was heated at 100°C for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo and the residue was purified on a silica column to give tert-butyl 3-((6-bromopyridazin-3-yl)methyl)piperidine-1-carboxylate (162 mg).

Step 3: Combine 3-((6-bromopyridazin-3-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (50 mg, 1.0 eq), (2-fluoro-6-hydroxy-4- Methylphenyl)boronic acid (31 mg, 1.3 eq), PdCl ₂ (dppf) (9 mg, 0.1 eq) and Na ₂ CO ₃ (30 mg, 2.0 eq) in dioxane (5 mL) and water (2 mL). The mixture was heated at 100°C for 8 hours. The crude mixture was purified on a silica gel column to obtain 3-((6-(2-fluoro-6-hydroxy-4-methylphenyl)pyridazin-3-yl)methyl)piperidine-1-carboxylic acid. Tributyl ester (41 mg).

Step 4: 3-((6-(2-Fluoro-6-hydroxy-4-methylphenyl)pyridazin-3-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (41 mg) Treat with 4N HCl in dioxane (1 mL). The mixture was stirred at room temperature for 15 minutes and concentrated in vacuo to give 3-fluoro-5-methyl-2-(6-(piperidin-3-ylmethyl)pyridazin-3-yl)phenol HCl salt ( 35 mg).

Step 5: Under the reaction conditions described in Step 5 of Example 1, from 3-fluoro-5-methyl-2-(6-(piperidin-3-ylmethyl)pyridazin-3-yl)phenol ( 35 mg) to obtain 3-fluoro-5-methyl-2-(6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)phenol (12 mg) ( Compound 7 ) . ESI-MS (EI ⁺ , m/z): 316.3. Example 8 : Synthesis of 3- fluoro -2-(6-( hydroxy (1- methylpiperidin -3- yl ) methyl ) pyridazin -3- yl )-5- methylphenol ( compound 8)

Step 1: Combine 3-((6-bromopyridazin-3-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 1.0 eq), SeO ₂ (4.0 eq) in CH ₃ CN (2 mL) was heated in a microwave reactor at 135°C for 8 hours. The mixture was cooled to room temperature, quenched with concentrated _NH4Cl , and extracted with DCM. The solvent was removed in vacuo and the residue was purified on a silica column to give 3-(6-hydroxypyridazine-3-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (48 mg).

Step 2: Dissolve tert-butyl 3-(6-hydroxypyridazine-3-carbonyl)piperidine-1-carboxylate (40 mg, 1.0 eq) and DMAP (40 mg) in DCM (2 mL) at 0°C. ) and pyridine (1 mL). At 0 °C, Tf ₂ O (2.0 eq) in DCM (1 mL) was added dropwise. The resulting mixture was stirred at room temperature for 15 hours. The reaction was quenched with water and extracted with DCM. The solvent was removed in vacuo and the residue was purified on a silica column to give 3-(6-(((trifluoromethyl)sulfonyl)oxy)pyridazine-3-carbonyl)piperidine-1- Tert-butyl formate (26 mg).

Step 3: Combine 3-(6-(((trifluoromethyl)sulfonyl)oxy)pyridazine-3-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (26 mg, 1.0 eq), ( 2-Fluoro-6-hydroxy-4-methylphenyl)boronic acid (1.5 eq), PdCl ₂ (dppf) (0.1 eq) and Na ₂ CO ₃ (2.0 eq) in toluene (3 mL) and water (1 mL ). The mixture was heated at 85°C for 8 hours. The mixture was cooled to room temperature and purified on a silica gel column to obtain 3-(6-(2-fluoro-6-hydroxy-4-methylphenyl)pyridazine-3-carbonyl)piperidine-1-carboxylic acid. Tributyl ester (15 mg).

Step 4: 3-(6-(2-Fluoro-6-hydroxy-4-methylphenyl)pyridazine-3-carbonyl)piperidine-1 in DCM (1 mL) at room temperature. -Tert-butyl formate (15 mg) was treated with TFA (1 mL) for 20 min. The solvent was removed in vacuo to give 3-fluoro-2-(6-(hydroxy(piperidin-3-yl)methyl)pyridazin-3-yl)-5-methylphenol TFA salt (18 mg).

Step 5: Under the reaction conditions described in Example 1 step 5, from 3-fluoro-2-(6-(hydroxy(piperidin-3-yl)methyl)pyridazin-3-yl)-5-methyl ylphenol TFA salt (18 mg) to obtain 3-fluoro-2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-5-methylphenol ( compound 8 ) (9 mg). ESI-MS (EI ⁺ , m/z): 332.3. Example 9 : Synthesis of 2-(4-( hydroxy (1- methylpiperidin -3- yl ) methyl ) phthalazin -1- yl )-5-( trifluoromethyl ) phenol ( compound 9)

Step 1: Combine 3-((9-borobicyclo[3.3.1]nonan-9-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 1.0 eq), 1,4-di Chlorophthalazine (250 mg, 2.0 eq), PdCl ₂ (dppf) (40 mg, 0.1 eq) and Na ₂ CO ₃ (135 mg, 2.0 eq) in dioxane (15 mL) and water (5 mL) merge. The mixture was heated at 100°C for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo and the residue was purified on a silica column to give tert-butyl 3-((4-chlorophthalazin-1-yl)methyl)piperidine-1-carboxylate (85 mg).

Step 2: Combine 3-((4-chlorophthalazin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (80 mg, 1.0 eq), (2-hydroxy-4-(trifluoromethyl) Phyl)phenyl)boronic acid (68 mg, 1.5 eq), PdCl ₂ (dppf) (15 mg, 0.1 eq) and Na ₂ CO ₃ (48 mg, 2.0 eq) in dioxane (5 mL) and water (2 mL). The mixture was heated at 100°C for 8 hours. The mixture was cooled to room temperature and purified on a silica column to obtain 3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)methyl)piperidine- 1-tert-Butylcarboxylate (38 mg).

Step 3: 3-((4-(2-Hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)methyl)piper in DCM (1 mL) at room temperature. Tert-butylpyridine-1-carboxylate (38 mg) was treated with TFA (1 mL) for 15 min. The mixture was concentrated in vacuo to give 2-(4-(piperidin-3-ylmethyl)phthalazin-1-yl)-5-(trifluoromethyl)phenol TFA salt (42 mg).

Step 4: Under the reaction conditions described in Step 5 of Example 1, prepare TFA from 2-(4-(piperidin-3-ylmethyl)phthalazin-1-yl)-5-(trifluoromethyl)phenol Salt (42 mg) gave 2-(4-(hydroxy(1-methylpiperidin-3-yl)methyl)phthalazin-1-yl)-5-(trifluoromethyl)phenol (18 mg) ( Compound 9 ). ESI-MS (EI ⁺ , m/z): 402.2. Example 10 : Synthesis of 2-(6-( hydroxy ( pyridin -3- yl ) methyl )-4- methylpyridazin -3- yl )-5-( trifluoromethyl ) phenol ( compound 10)

Step ₁ : To degassed 3,6-dichloro-4-methylpyridazine (8.2 g, 50 mmol) and 3- To a solution of pyridylacetonitrile (6.1 g, 52 mmol) was added NaH (4.2 g, 105 mmol, 60%) portionwise. The reaction mixture was stirred at 0°C for 1 hour. m-CPBA (12 g, 72%) was added to the solution in portions over 10 min at 0°C. The reaction mixture was diluted with EtOAc (200 mL) and stirred at 0 °C for an additional 10 min. Saturated _NaHCO3 (100 mL) was added at 0°C and the mixture was stirred for 10 min. The mixture was diluted with water (200 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3×100 mL), saturated _NaHCO3 (100 mL), brine (100 mL) and _dried over _Na2SO4 . The solvent was concentrated in vacuo. The solid was sonicated in EtOAc (50 mL), filtered, washed with EtOAc/hexane (1:1) (20 mL), and then in EtOAc/hexane (1:1) (50 mL) at 50 °C. Puree for 30 minutes. The mixture was cooled to room temperature and the solid was removed by filtration to give (6-chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanone ( A-10 ) (4.2 g). The combined mother liquors were concentrated in vacuo and purified on a silica column to obtain (6-chloro-4-methylpyridazin-3-yl)(pyridin-3-yl)methanone ( B-10 ) (1.3 g ).

Step 2: Dissolve (6-chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanone ( A-10 ) (1.0 g, 1.0 eq) in MeOH (20 mL) and THF (20 mL) and cool to 0°C. _NaBH4 (81 mg, 0.5 eq) was added at 0°C. The resulting mixture was stirred at 0°C for 15 minutes. The reaction was quenched with saturated _NaHCO3 and then extracted with ethyl acetate. The solvent was removed in vacuo to give (6-chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanol (1.0 g) which was used without further purification.

Step 3: Combine (6-chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanol (1.0 g, 1.0 eq), (2-hydroxy-4-(trifluoromethyl)benzene (1.14 g, 1.3 eq), PdCl ₂ (dppf) (0.28 g, 0.1 eq) and Na ₂ CO ₃ (0.9 g, 2.0 eq) in dioxane (20 mL) and water (5 mL) merge. The resulting mixture was heated at 100°C for 8 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water, brine and concentrated in vacuo. The residue was purified on a silica column to obtain 2-(6-(hydroxy(pyridin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol ( Compound 10 ) (0.75 g). ESI-MS (EI ⁺ , m/z): 362.2. Example 11 : Synthesis of 2-(6-( hydroxy (1- methylpiperidin -3- yl ) methyl )-4- methylpyridazin -3- yl )-5-( trifluoromethyl ) phenol ( compound 11)

Step 1: To 2-(6-(hydroxy(pyridin-3-yl)methyl)-4-methylpyridazin-3-yl)-5 in MeOH (150 mL) and water (1 mL) -(Trifluoromethyl)phenol ( compound 10 ) (0.7 g, 1.0 eq) was added to a solution of PtO ₂ (0.35 g, 0.8 eq) and (Boc) ₂ O (0.47 g, 1.1 eq). The mixture was degassed with bubbling _N2 gas for 20 minutes and then hydrogenated under _H2 (balloon) at room temperature for 1.5 hours. The _H2 balloon was then removed and the mixture was stirred at room temperature overnight. The catalyst was removed by filtration and the solvent was concentrated in vacuo. The residue was purified on a silica column to obtain 3-(hydroxy(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyrazin-3-yl)methyl)piper tert-Butylpyridine-1-carboxylate (0.35 g).

Step 2: To 3-(hydroxy(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl in DCM (5 mL) ), TFA (8 mL) was added to a solution of piperidine-1-carboxylic acid tert-butyl ester (300 mg). The mixture was stirred at room temperature for 25 minutes. The mixture was concentrated in vacuo. The residue was suspended in saturated NaHCO ₃ and then extracted with DCM (5 x 20 mL). The combined extracts were concentrated in vacuo to give 2-(6-(hydroxy(piperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(tris Fluoromethyl)phenol (180 mg) was used without further purification.

Step 3: To 2-(6-(hydroxy(piperidin-3-yl)methyl)-4-methylpyridazin-3-yl) in 1,2-dichloroethane (15 mL) To a solution of -5-(trifluoromethyl)phenol (180 mg, 1.0 eq) was added HCHO (48 mg, 37% in water, 1.2 eq) and 2 drops of AcOH. The mixture was stirred at room temperature for 30 minutes and NaBH(AcO) ₃ (165 mg, 1.5eq) was added. The resulting mixture was stirred at room temperature for 30 minutes, quenched with saturated _NaHCO3 , and stirred at room temperature for 10 minutes. The mixture was extracted with DCM (4 x 25 mL). The combined extracts were concentrated in vacuo. The residue was purified on a silica gel column to obtain 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)- as a white solid. 5-(Trifluoromethyl)phenol ( Compound 11 ) (118 mg). ESI-MS (EI ⁺ , m/z): 382.2. Example 12 : Synthesis of 2-(6-( hydroxy (1- methylpiperidin -3- yl ) methyl )-5- methylpyridazin -3- yl )-5-( trifluoromethyl ) phenol ( compound 12)

Compound 12 was prepared by the procedure described in Example 11 starting with B-10 from Example 10. ESI-MS (EI ⁺ , m/z): 382.3. Example 13 : Synthesis of (6-(2- hydroxy- 4-( trifluoromethyl ) phenyl )-5- methylpyridazin- 3- yl )( pyridin -3- yl ) methanone ( compound 13)

(6-Chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanone (30 mg, 1.0 eq), (2-hydroxy-4-(trifluoromethyl)phenyl) Boric acid ( A-10 ) (35 mg, 1.3 eq), PdCl ₂ (dppf) (8 mg, 0.1eq) and Na ₂ CO ₃ (28 mg, 2.0 eq) in dioxane (5 mL) and water (2 mL). The resulting mixture was heated at 100°C for 8 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water, brine and concentrated in vacuo. The residue was purified on a silica column to obtain (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(pyridin-3-yl)methyl ketone ( compound 13 ) (26 mg). ESI-MS (EI ⁺ , m/z): 360.0. Example 14 : Synthesis of (6-(2- hydroxy- 4-( trifluoromethyl ) phenyl )-5- methylpyridazin -3- yl )(1- methylpiperidin -3- yl ) methanone ( Compound 14)

Step 1: Combine (6-chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanol (1.2 g, 1.0 eq), (2-methoxy-4-(trifluoromethyl) )Phenyl)boronic acid (1.45 g, 1.3 eq), PdCl ₂ (dppf) (325 mg, 0.1 eq) and Na ₂ CO ₃ (1.2 g, 2.0 eq) in dioxane (30 mL) and water (5 mL ). The resulting mixture was heated at 100°C for 12 hours. The reaction mixture was diluted with ethyl acetate (120 mL), washed with water, brine and concentrated in vacuo. The residue was purified on a silica gel column to obtain (6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(pyridin-3-yl) ) methanol (1.18 g).

Step 2: To (6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3- in MeOH (250 mL) and water (2 mL) PtO ₂ (530 mg, 0.8 eq) and (Boc) ₂ O (720 mg, 1.1 eq) were added to a solution of (pyridin-3-yl)methanol (1.1 g, 1.0 eq). The mixture was degassed by bubbling _N2 gas for 20 minutes and then hydrogenated under _H2 (balloon) at room temperature for 1.5 hours. The _H2 balloon was then removed and the mixture was stirred at room temperature overnight. The catalyst was removed by filtration and the solvent was concentrated in vacuo. The residue was purified on a silica column to obtain 3-(hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl ) piperidine-1-carboxylic acid tert-butyl ester (1.05 g).

Step 3: Add 3-(hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl))-5-methylpyridazine in anhydrous DCM (30 mL) at 0 °C. To a solution of -3-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (1 g, 1.0 eq) was added DMP (1.1 g, 1.2 eq). The reaction mixture was stirred at 0°C for 1 hour and then quenched with saturated _NaHCO3 . The solvent was removed in vacuo and the residue was purified on a silica column to obtain 3-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3 -Carbonyl)piperidine-1-carboxylic acid tert-butyl ester (890 mg).

Step 4: Add 3-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methyl in anhydrous DCM (30 mL) at ₀ °C under N To a solution of tert-butylpyridazine-3-carbonyl)piperidine-1-carboxylate (890 mg, 1.0 eq) was added BBr ₃ (5 eq). The mixture was stirred at 0°C for 1 hour and then at room temperature for 6 hours. The reaction was quenched with 0 °C water, stirred at room temperature for 30 min, then adjusted to pH ~10 by adding saturated NaHCO ₃ and extracted with DCM (3 x 50 mL). (Boc) _2O (425 mg, 1.0 eq) was added to the DCM solution and the mixture was stirred at room temperature for 1 hour. The crude mixture was purified on a silica column to obtain 3-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (810 mg).

Step 5: 3-(6-(2-Hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-carbonyl)piperidine-1 in DCM (2 mL) -Tert-butyl formate (50 mg) was treated with TFA (1 mL). The mixture was stirred at room temperature for 30 minutes and concentrated in vacuo to give (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(piperidine- 3-yl)methanone TFA salt (62 mg).

Step 6: Under the reaction conditions described in Step 5 of Example 1, from (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(piperazine) Tridin-3-yl)methanone TFA salt (62 mg) gave (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methyl ylpiperidin-3-yl)methanone (28 mg) ( Compound 14 ). ESI-MS (EI ⁺ , m/z): 380.0. Example 15 : Synthesis of 2-(6-(1- hydroxy- 1-(1- methylpiperidin -3- yl ) ethyl )-4- methylpyridazin -3- yl )-5-( trifluoromethyl base ) phenol ( compound 15)

Dissolve (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methyl) in anhydrous THF (2 mL) at 0 °C. A solution of piperidin-3-yl)methanone ( compound 14 ) (22 mg, 1.0 eq) was treated with MeMgBr (2N, 0.12 mL, 4.0 eq). The mixture was stirred at room temperature for 1 hour, then quenched with saturated _NH4Cl and extracted with DCM (4 x 20 mL). The combined extracts were concentrated and the residue was purified on HPLC to give 2-(6-(1-hydroxy-1-(1-methylpiperidin-3-yl)ethyl)-4-methylpyridazine -3-yl)-5-(trifluoromethyl)phenol (9 mg) ( Compound 15 ). ESI-MS (EI ⁺ , m/z): 396.2. Example 16 : Synthesis of (6-(2- hydroxy -4-( trifluoromethyl ) phenyl )-5- methylpyridazin -3- yl )(1- methylpiperidin -3- yl ) methanone oxime ( Compound 16)

To ZMG-3193 (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methyl) in anhydrous EtOH (2 mL) To a solution of piperidin-3-yl)methanone ( compound 14 ) (20 mg, 1.0 eq) was added NH ₂ OH (1.2 eq) and 2 drops of AcOH. The resulting mixture was heated at 50°C for 5 hours and concentrated to dryness. The residue was purified on a silica gel column to obtain (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methylpiperidine- 3-yl)methanone oxime (7 mg) ( Compound 16 ). ESI-MS (EI ⁺ , m/z): 395.1. Example 17 : Synthesis of 2-(6-((S) -hydroxy ((R)-1- methylpiperidin -3- yl ) methyl )-4- methylpyridazin -3- yl )-5-( Trifluoromethyl ) phenol ( Compound 17A) , 2-(6-((R) -hydroxy ((R)-1- methylpiperidin -3- yl ) methyl )-4- methylpyridazine -3 -yl )-5-( trifluoromethyl ) phenol ( compound 17B) , 2-(6-((R) -hydroxy ( (S)-1- methylpiperidin -3- yl ) methyl )-4 -Methylpyridazin -3- yl )-5-( trifluoromethyl ) phenol ( compound 17C) , 2-(6-((S) -hydroxy ((S)-1- methylpiperidine - 3- methyl ) -4- methylpyridazin -3- yl )-5-( trifluoromethyl ) phenol ( compound 17D )

The product of Example 14 step 4, 3-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-carbonyl)piperidine-1-carboxylate (250 mg) was subjected to SFC chiral separation to obtain compound 17-1 (94 mg) and compound 17-2 (97 mg).

Under the reaction conditions described in step 3 of Example 1, compound 17-1 (90 mg) generates intermediate alcohol (90 mg), which is separated by a counter-chip column to obtain compound 17-1A (36 mg) and compound 17-1B (32 mg). Compound 17-1A (36 mg) was deprotected using the method described in Step 4 of Example 7. The resulting amine intermediate HCl salt was subjected to reductive amination using the method described in step 5 of Example 1 to provide compound 17A (16.4 mg). ESI-MS (EI ⁺ , m/z): 382.1. The absolute stereochemistry of compound 17A was confirmed by single crystal x-ray crystallography. Compound 17B (13 mg) was obtained from compound 17-1B using the same chemistry. ESI-MS (EI ⁺ , m/z): 382.2.

In a similar manner, compound 17-2 (95 mg) was reduced and subjected to SFC chiral separation to obtain compound 17-2A (38 mg) and compound 17-2B (35 mg). Deprotection and reductive amination of compound 17-2A (38 mg) and compound 17-2B (35 mg) afforded compound 17C (16 mg) and compound 17D (13 mg), respectively. Compound 17C: ESI-MS (EI ⁺ , m/z): 382.2. Compound 17D: ESI-MS (EI ⁺ , m/z): 382.2. Example 18 : Synthesis of 2-(6-((S) -hydroxy ((R)-1- methylpiperidin -3- yl ) methyl -d)-4- methylpyridazin -3- yl )-5 -( Trifluoromethyl ) phenol ( compound 18)

Under the reaction conditions described in step 3 of Example 1 and replacing d4-MeOD and NaBD ₄ , to d4-MeOD (2 mL) containing peak 17-1 (120 mg) was added NaBD ₄ (0.5 eq), the intermediate alcohol (119 mg) was obtained, which was separated by a counter-chip column to obtain peak 18-1A (65 mg) and peak 18-1B (40 mg). Intermediate peak 18-1B (40 mg) was treated with 4N HCl to give the amine intermediate, which was reductively aminated with HCHO (1.2 eq) in the presence of NaBH(AcO) ₃ (1.5 eq) to give 2-( 6-((S)-Hydroxy((R)-1-methylpiperidin-3-yl)methyl-d)-4-methylpyridazin-3-yl)-5-(trifluoromethyl) Phenol (28 mg) ( compound 18 ). ESI-MS (EI ⁺ , m/z): 383.2. Example 19 : Synthesis of 2-(6-( hydroxy (1- methylpiperidin -3- yl ) methyl ) pyridazin -3- yl )-3,5 -dimethylphenol ( compound 19)

Step ₁ : To degassed 3,6-dichloropyridazine (3 g, 20 mmol) in DMF (30 mL), pyridin-3-yl-acetonitrile ( To a solution of 2.5 g, 21 mmol), NaH (1.68 g, 42 mmol, 60%) was added portionwise. The mixture was stirred at 0°C for 1 hour. mCPBA (4.8 g, 20 mmol, 72%) was added portionwise and the mixture was diluted with EtOAc (200 mL). The mixture was washed with water, aqueous _NaHCO3 and brine, dried over _Na2SO4 , filtered and _concentrated . The residue was triturated with hexane/EtOAc to give (6-chloropyridazin-3-yl)(pyridin-3-yl)methanone (2.3 g).

Step 2: Under the reaction conditions described in Step 2 of Example 10, (6-chloropyridazine-3-yl)(pyridin-3-yl)methanone (1.0 g) was obtained. -(pyridin-3-yl)methanol (1.0 g).

Step 3: Combine (6-chloropyridazin-3-yl)(pyridin-3-yl)methanol (600 mg, 1.0 eq), (2-hydroxy-4,6-dimethylphenyl)boronic acid (585 mg , 1.3 eq), PdCl ₂ (dppf) (160 mg, 10%) and Na ₂ CO ₃ (600 mg, 2.0 eq) were combined in dioxane (30 mL) and water (5 mL). The resulting mixture was heated at 100°C for 8 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water, brine and concentrated in vacuo. The residue was purified on a silica column to obtain 2-(6-(hydroxy(pyridin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethylphenol (625 mg).

Step 4: Under the reaction conditions described in Step 4 of Example 1, from 2-(6-(hydroxy(pyridin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethylphenol (100 mg) gave 2-(6-(hydroxy(piperidin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethylphenol (120 mg), which was used without further purification. That.

Step 5: Under the reaction conditions described in Step 5 of Example 1, from 2-(6-(hydroxy(piperidin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethyl Phenol (120 mg, 1.0 eq) gave 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethylphenol (35 mg ) ( compound 19 ). ESI-MS (EI ⁺ , m/z): 328.1. Example 20 : Synthesis of 2-(6-( hydroxy (1- methylpiperidin -3- yl ) methyl ) pyridazin -3- yl )-3- methyl -5-( trifluoromethyl ) phenol ( compound 20)

Step 1: Add 3-methyl-5-(trifluoromethyl)aniline (2.63 g, 15 mmol) to a solution of concentrated _H2SO4 (30 mL) in _water (150 mL) and add The mixture was cooled to 0°C. _NaNO2 (1.1 g, 16 mmol) in water (10 mL) was added dropwise to the mixture and the reaction was stirred at 0°C for 1 hour. _{Concentrated H2SO4} (30 mL) was added and the mixture was heated to 90°C for 5 hours. The mixture was cooled to room temperature and extracted with EtOAc. _The combined organic layers were washed with brine, dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography to obtain 3-methyl-5-(trifluoromethyl)phenol (2.2 g).

Step 2: To a solution of 3-methyl-5-(trifluoromethyl)phenol (2.1 g, 12 mmol) in toluene (60 mL) was added NaH (0.96 g, 24 mmol, 60%). The suspension was stirred at 0°C for 30 minutes. Iodine (12 mmol) was added slowly in portions and the mixture was stirred at 0 °C for 3 h. The mixture was diluted with water (50 mL) and acidified to pH 5 with 2N HCl. The organic phase was separated and the aqueous phase was extracted with EtOAc. _The combined organic layers were washed with brine, dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography to obtain 2-iodo-3-methyl-5-(trifluoromethyl)phenol (2.7 g).

Step 3: Add (chloromethoxy)methane (0.8 g, 10 mmol) dropwise to 2-iodo-3-methyl-5-(trifluoromethyl) in DMF (10 mL) at 0 °C. base) in a suspension of phenol (2.4 g, 8 mmol) and Cs ₂ CO ₃ (3.26 g, 10 mmol). The reaction mixture was warmed to room temperature over 2 hours and diluted with EtOAc (50 mL). The mixture was washed with water and _brine , dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography to obtain 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (2.3 g).

Step 4: Add 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (1.02 g, 3 mmol) in anhydrous DMF (10 mL), A mixture of bis(pinacolyl)diborane (0.9 g, 3.6 mmol), Pd(OAc) ₂ (67 mg, 0.3 mmol) and KOAc (0.6 g, 6 mmol) was stirred at 100°C for 10 hours. The mixture was diluted with EtOAc, washed with water (3x), brine and _dried over _Na2SO4 . The solvent was evaporated and the residue was purified by flash chromatography to give 2-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4, 5,5-Tetramethyl-1,3,2-dioxaborolane (605 mg).

Step 5: Combine (6-chloropyridazin-3-yl)(pyridin-3-yl)methanol (120 mg, 1.0 eq), 2-(2-(methoxymethoxy)-6-methyl-4 -(Trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 eq), PdCl ₂ (dppf) (0.1 eq ) and Na ₂ CO ₃ (2.0 eq) were combined in dioxane (10 mL) and water (2 mL). The resulting mixture was heated at 100°C for 12 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water, brine and concentrated in vacuo. The residue was purified on a silica gel column to obtain (6-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)pyridin-3-yl)(pyridine -3-yl)methanol (115 mg).

Step 6: Add (6-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl) in MeOH (100 mL) and water (1 mL). To a solution of oxazin-3-yl)(pyridin-3-yl)methanol (110 mg, 1.0 eq) was added PtO ₂ (0.8 eq) and (Boc) ₂ O (1.1 eq). The mixture was degassed with bubbling _N2 gas for 20 min and then hydrogenated under _H2 (balloon) at room temperature for 1.5 h. The _H2 balloon was then removed and the mixture was stirred at room temperature overnight. The catalyst was removed by filtration and the solvent was concentrated in vacuo. The residue was purified on a silica column to obtain 3-(hydroxy(6-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)pyridazine-3- tert-butyl)methyl)piperidine-1-carboxylate (92 mg).

Step 7: To 3-(hydroxy(6-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)pyridazine in anhydrous DCM at 0°C To a solution of -3-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (90 mg, 1.0 eq) was added DMP (1.2 eq). The reaction mixture was stirred at 0°C for 1 hour and then quenched with saturated _NaHCO3 . The solvent was concentrated in vacuo and the residue was purified on a silica column to obtain 3-(6-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl) Pyrazine-3-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (62 mg).

Step 8: Add 3-(6-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl) in anhydrous DCM ( ₁ mL) at 0 °C under N To a solution of tert-butyl)phenyl)pyridazine-3-carbonyl)piperidine-1-carboxylate (58 mg, 1.0 eq) was added TFA (1 mL). The mixture was stirred at 0°C for 1 hour and then at room temperature overnight. The reaction was concentrated in vacuo. The residue was suspended in water and adjusted to pH approximately 10 by adding saturated NaHCO ₃ and then extracted with DCM (3 x 50 mL). The combined organic layers were concentrated and the residue was purified on a silica gel column to obtain (6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)( Piperidin-3-yl)methanone (28 mg).

Step 9: Under the reaction conditions described in Example 1, Step 5, from (6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)( Piperidin-3-yl)methanone (18 mg) gave 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)pyridin-3-yl)-3-methyl-5 -(Trifluoromethyl)phenol ( Compound 20 ) (11 mg). ESI-MS (EI ⁺ , m/z): 382.3. Example 21 : Synthesis of 3-((6-(2- hydroxy -4-( trifluoromethyl ) phenyl ) pyrazin -3- yl ) methylpiperidin -3- ol ( Compound 21)

Step 1: Add 3- _chloro -6-methylpyridazine (1.0 g, 7.81 mmol), (2-methoxy-4- A solution of (trifluoromethyl)phenyl)boronic acid (2.05 g, 9.37 mmol), Pd(dppf)Cl ₂ (570 mg, 0.78 mmol) and Na ₂ CO ₃ (1.65 g, 15.62 mmol) was prepared at 90°C in N _2. Stir under atmosphere. The mixture was quenched with brine (100 mL) and then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (3 _x 100 mL), dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3-(2-methoxy-4-(trifluoromethyl)phenyl)-6-methylpyridazine (1.91 g, 91%).

Step 2: To 3-(2-methoxy-4-(trifluoromethyl)phenyl)-6-methylpyridazine (1.0 g) in anhydrous THF (25 mL) at -50 °C, n-BuLi (2.2 mL, 5.59 mmol) was added dropwise to the solution. The reaction mixture was stirred at -50°C for 30 min, and then tert-butyl 3-pendantoxypiperidine-1-carboxylate (1.48 g, 7.46 mmol) in anhydrous THF (15 mL) was added dropwise at -50°C. . The mixture was gradually warmed to room temperature. After 1 hour, the mixture was quenched with NH ₄ Cl (aq) (100 mL) and then extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with brine (100 mL), dried over _Na2SO4 , and concentrated under reduced pressure _. The residue was purified by silica gel column chromatography to obtain 3-hydroxy-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl tert-butyl)piperidine-1-carboxylate (1.32 g, 76%).

Step 3: Add 3-hydroxy-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl in anhydrous DCM (25 mL). base) piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.43 mmol) and cooled to -78°C. Add BBr ₃ (1.2 mL, 1.28 mmol) dropwise. The mixture was gradually warmed to room temperature and then stirred at room temperature for 6 hours. The mixture was quenched with NaHCO ₃ (aq) (100 mL) and then extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over _Na2SO4 , and concentrated under reduced pressure _. The residue was purified by preparative HPLC to obtain 3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)piperidin-3-ol ( Compound 21 ) (13 mg, 9%). ESI-MS(EI ⁺ , m/z): 354.2. Example 22 : Synthesis of 2-(4-(1-( piperidin -3- yl ) ethyl ) phthalazin -1- yl )-5-( trifluoromethyl ) phenol ( compound 22)

Step 1: Add LiHMDS (1.0 M in THF) (21.8 mL, 21.8 mmol) to THF (50 mL) at -78 °C under nitrogen. A solution of 1-(tetrahydro-2 H -pyran-4-yl)ethanone (4.5 g, 19.8 mmol) in THF (10 mL) was added and the mixture was stirred at -78 °C under nitrogen for 1.5 h. . N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonate in THF (10 mL) was added over 20 min. A solution of amide (7.78 g, 21.8 mmol). The mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction was quenched with _NaHCO3 and the crude product was extracted with EtOAc. The combined organic extracts were washed with brine, dried _{over Na2SO4} and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain 3-(1-(((trifluoromethyl)sulfonyl)oxy)vinyl)piperidine-1-carboxylic acid tert-butyl ester (6.17 g , 87%).

Step 2: To tert-butyl 3-(1-(((trifluoromethyl)sulfonyl)oxy)vinyl)piperidine-1-carboxylate (6.17 g) in toluene (50 mL), To a solution of 17.2 mmol), bis(pinacolyl)diboron (6.32 g, 25.8 mmol) was added, followed by triphenylphosphine (451.1 mg, 1.72 mmol), potassium phenolate (3.4 g, 25.8 mmol) and dichloro Bis(triphenylphosphine)palladium(II) (1.21 g, 1.72 mmol). The resulting mixture was allowed to stir at 55°C for 3 hours. The resulting mixture was cooled to room temperature and stirred overnight. The resulting mixture was diluted with saturated aqueous _NaHCO3 solution and EtOAc. The layers were separated and the organic layer was washed with _brine , dried over _Na2SO4 , filtered and evaporated to dryness. The residue was purified by silica gel column chromatography to obtain 3-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )Vinyl)piperidine-1-carboxylic acid tert-butyl ester (1.81 g, 31%).

Step 3: To 3-(1-(4,4,5,5-tetramethyl-1,3, in 1,4-dioxane (32 mL) and aqueous H ₂ O (8 mL) To a solution of 2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 3.3 mmol) was added 2-(4-chlorophthalazine-1- (1.0 g, 3.0 mmol), Pd(PPh ₃ ) ₄ (346.5 mg, 0.3 mmol) and K ₂ CO ₃ (829.2 mg, 6.0 mmol). The reaction mixture was stirred at 90°C under nitrogen atmosphere for 3 hours. The reaction mixture was extracted with EtOAc. _The organic solution was washed with brine, dried over _Na2SO4 , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3-(1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)vinyl)piperidine -Tert-butyl 1-carboxylate (392 mg, 26%).

Step 4: To 3-(1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)ethenyl)piperidine- in EtOAc (5 mL) To a solution of tert-butyl 1-formate (145 mg, 0.29 mmol) was added Pd/C (100 mg). The reaction mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The reaction mixture was filtered and washed with MeOH. The residue was concentrated in vacuo. The residue was purified by silica column chromatography to obtain 3-(1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)ethyl)piperidine -Tert-butyl-1-carboxylate (72.4 mg, 48%).

Step 5: 3-(1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)ethyl)piperidine- in DCM (8 mL) A solution of tert-butyl 1-formate (72.4 mg, 0.14 mmol) was cooled to 0°C. TFA (1 ml) was added slowly dropwise and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 2-(4-(1-(piperidin-3-yl)ethyl)phthalazin-1-yl)-5-(tris Fluoromethyl)phenol ( compound 22 ) (9.5 mg, 14%). ESI-MS(EI ⁺ , m/z): 402.3. Example 23 : Synthesis of 3-( hydroxy (6-(2- hydroxy -4-( trifluoromethyl ) phenyl ) pyridazin -3- yl ) methyl -1- methylpiperidin -4- one ( compound 23 )

Step 1: To a solution of 6-chloropyridazine-3-carboxylic acid methyl ester (30.0 g, 174 mmol) in toluene (450 mL) and aqueous _H2O (50 mL) was added (2-methoxy -4-(Trifluoromethyl)phenyl)boronic acid (42.0 g, 191 mmol), Pd(dppf) _Cl2 (10.0 g, 17.4 mmol) and _K3PO4 ( _73.9 g, 348 mmol). The resulting mixture was stirred at 100°C for 2 hours. The reaction solution was diluted with water, extracted with _EtOAc , dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain 6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazine-3-carboxylic acid methyl ester (31.0 g, 57%).

Step 2: To methyl 6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazine-3-carboxylate in THF (400 mL) and MeOH (80 mL) at 0 °C To a solution of the ester (25.0 g, 80.1 mmol) was slowly added _LiBH4 (60 mL, 2M in THF, 1.5 eq.). The resulting mixture was stirred at room temperature under _N2 for 1 h. The reaction solution was quenched with water, extracted with EtOAc, dried over _Na2SO4 , filtered and concentrated in vacuo to obtain (6-(2-methoxy-4-(trifluoromethyl)phenyl ₎ as a white solid Pyrazin-3-yl)methanol (20.0 g, 88%).

Step 3: To (6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methanol (19.0 mg) in DCM (500 mL) at 0 °C. To a solution of 66.9 mmol), Dess-Martin periodane (42.4 g, 100 mmol) was slowly added. The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was quenched with water, extracted with _DCM , dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain 6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazine-3-carbaldehyde (7.0 g, 37%) as a yellow solid ).

Step 4: To 6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazine-3-one in 1-methylpiperidin-4-one (960 mg, 8.5 mmol) To a solution of formaldehyde (500 mg, 1.7 mmol) was added (S)-proline (20 mg, 0.17 mmol). The resulting mixture was stirred at room temperature under _N2 for 16 h. The reaction solution was diluted with DCM and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain 3-(hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl) as a white solid) Methyl-1-methylpiperidin-4-one (450 mg, 67%).

Step 5: Add 3-(hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl))pyridazine- in DCM ( _0.5 mL) at 0 °C under N To a solution of 3-yl)methyl-1-methylpiperidin-4-one (30 mg, 0.08 mmol), BBr ₃ (0.5 mL) was added dropwise. The resulting mixture was stirred at 40°C for 2 hours. The reaction solution was Diluted with MeOH and concentrated in vacuo. The residue was purified by preparative HPLC to give 3-(hydroxy(6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazine-) as a brown solid 3-yl)methyl-1-methylpiperidin-4-one ( compound 23 ) (7.5 mg, 26%, reverse: same = 2:1). ESI-MS (EI ⁺ , m/z): 382.15 .Example 24 : Synthesis of (R)-(6-(2- methoxy- 4-( trifluoromethyl ) phenyl )-5- methylpyridazin- 3- yl )((R)-1- methyl (piperidin -3- yl ) methanol ( compound 24)

Step ₁ : In a sealed tube, add 3-methylfuran (1.0 g, 1.0 eq), NBS (2.3 g, 1.05 eq) and AIBN (0.16 g, 0.08 eq) in degassed anhydrous dioxin Combine with alkane (25 mL) and heat at 50°C for 2 hours to obtain a solution of 2-bromo-3-methylfuran in dioxane, which is used directly in the next step.

Step 2: To the solution of 2-bromo-3-methylfuran, add (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (3.0 g, 1.12 eq), Cs ₂ CO ₃ (10 g, 2.5 eq), Pd(PPh ₃ ) ₄ (0.7 g, 0.05 eq) and degassed DI water (25 mL). The resulting mixture was heated at 110°C for 8 hours. The reaction mixture was cooled to room temperature and diluted with hexane (120 mL). The organic phase was separated and the aqueous phase was re-extracted with hexane (30 mL). The combined organic phases were washed with water (50 mL), brine (50 mL) and concentrated in vacuo. The residue was purified on a silica column to obtain 2-(2-methoxy-4-(trifluoromethyl)phenyl)-3-methylfuran (1.9 g, 61%) as an oil.

Step 3: To a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (5.0 g, 1.0 eq) in DMF (20 mL) was added HBTU (10.33 g, 1.25 eq), N,O-dimethylhydroxylamine hydrochloride (2.6 g, 1.2 eq), and triethylamine (9 mL, 3.0 eq). The resulting mixture was stirred at 0°C for 1 hour and then at room temperature for 5 hours. The reaction mixture was diluted with acetate (80 mL) and hexane (80 mL), and added with saturated aqueous NaHCO ₃ (50 mL), water (3 x 50 mL), HCl (0.5N, 50 mL), and brine (50 mL). mL) washing. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo to give (R)-3-(methoxy(methyl)aminomethanoyl)piperidine-1-carboxylic acid tert-butyl ester (5.4) as an oil g, 91%).

Step 4: Add 2-(2-methoxy-4-(trifluoromethyl)phenyl)-3- in anhydrous THF (25 mL) under _N at -30 °C for 5 min. To a solution of methylfuran (500 mg, 1.0 eq.), n-BuLi (2.5 M, 1.25 mL, 1.6 eq.) was added dropwise. After stirring for an additional 45 min at -30°C, (R)-3-(methoxy(methyl)aminomethyl)piperidine in THF (4 mL) was added dropwise at -30°C over 2 min. - A solution of tert-butyl 1-carboxylate (850 mg, 1.6 eq). The resulting mixture was stirred at -30°C for 30 minutes and then at room temperature for 2 hours. The reaction was quenched with saturated _NH4Cl (30 mL) at 0°C and extracted with DCM (2 x 50 mL). The combined organic phases were washed with brine and concentrated in vacuo. The crude mixture was purified on a silica column to obtain (R)-3-(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2-carbonyl)piper Tert-butylpyridine-1-carboxylate (749 mg, 82%, 100% ee).

Step 5: To (R)-3-(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl in DMF (0.3 mL) at 0 °C To a solution of furan-2-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (150 mg, 1.0 eq.), formic acid (150 mg, 10 eq.) and TEA (330 mg, 10 eq.) were added dropwise. The mixture was degassed by bubbling _N2 gas at room temperature for 2 minutes and then the catalyst ruthenium chloride (1+); [(1R,2R)-1,2-biphenyl-2-(3-phenyl) was added Propylamino)ethyl]-(4-methylphenyl)sulfonamide (6 mg, 0.03 eq). The resulting mixture was stirred at room temperature for 15 hours. The mixture was diluted with DCM (25 mL) and washed with water, saturated NaHCO ₃ and brine. The crude mixture was purified on a silica column to obtain (R)-3-((R)-hydroxy(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran -2-yl)Methyl)piperidine-1-carboxylic acid tert-butyl ester (138 mg, 92%, ca. 90% de).

Step 6: Dissolve (R)-3-((R)-hydroxy(5-(2-methoxy-4-(trifluoromethyl))benzene in THF (5 mL) and water (0.5 mL) A solution of tert-butyl)-4-methylfuran-2-yl)methyl)piperidine-1-carboxylate (80 mg, 1.0 eq) was stirred at -15°C (acetone-ice bath) for 10 minutes. Add solid NBS (40 mg, 1.3 eq) in portions. After stirring at -15°C for 30 minutes, hydrazine hydrate (86 mg, 10 eq) was added dropwise. The resulting mixture was stirred at 0°C for 1 hour and then at room temperature for 3 hours. The reaction was quenched with saturated aqueous NaHCO ₃ (10 mL) and extracted with DCM (2 x 15 mL). The combined organic phases were washed with brine and concentrated in vacuo. The crude mixture was purified on silica gel to give (R)-3-((R)-hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine- 3-yl)Methyl)piperidine-1-carboxylic acid tert-butyl ester (75 mg, 92%).

Step 7: To (R)-3-((R)-hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl))-5-methyl in DCM (1 mL) To a solution of tert-butylpyridazin-3-ylmethyl)piperidine-1-carboxylate (46 mg) was added HCl (4N in dioxane, 1 mL). The mixture was stirred at room temperature under _N2 for 20 min. The solvent was removed in vacuo to give the intermediate HCl salt, which was dissolved in MeOH (0.5 mL) and 1,2-dichloroethane (5 mL). Triethylamine (11 mg, 1.1 eq) was added to the mixture to neutralize the HCl salt. HCHO (37% in water, 12 mg, 1.5 eq) was added to the reaction mixture, followed by acetic acid (approximately 5 mg). The mixture was stirred at room temperature for 15 min, then NaBH(OAc) ₃ (50 mg, 2.5 eq) was added. The reaction was quenched with saturated _NaHCO3 (10 mL). The reaction mixture was extracted with mixed solvent (5% IPA in DCM) (2 x 20 mL). The crude product was purified on a silica column to obtain (R)-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(( R)-1-methylpiperidin-3-yl)methanol ( compound 24 ) (35 mg, 93%). ESI-MS (EI ⁺ , m/z): 396.1. Example 25 : Synthesis of 2-(6-((R)-((R)-1- cyclopropylpiperidin -3- yl )( hydroxy ) methyl )-4- methylpyridazin -3- yl )- 5-( trifluoromethyl ) phenol ( compound 25)

Step 1: Add (R)-tert-butyl 3-(methoxy(methyl)aminomethyl)piperidine-1-carboxylate (1.0 g) in DCM (5 mL) with HCl (4N in dioxane, 5 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo to give (R)-N-methoxy-N-methylpiperidine-3-carboxamide HCl salt (760 mg).

Step 2: Dissolve (R)-N-methoxy-N-methylpiperidine-3-carboxamide HCl salt in anhydrous MeOH (4 mL) and anhydrous THF (20 mL). At room temperature, DIEA (520 mg, 1.0 eq), 4A molecular sieve (1.0 g), (1-ethoxycyclopropoxy)trimethylsilane (2.0 g, 3.0 eq), NaBH ₃ CN were added to the solution. (700 mg, 3.0 eq) and AcOH (3.3 g, 15 eq). The resulting mixture was heated at 65 °C under N for ₂₀ h. The reaction was filtered through a pad of celite and quenched with saturated aqueous _NaHCO3 and extracted with DCM (2 × 60 mL). The combined organic phases were washed with brine. The crude mixture was purified on a silica column to give (R)-1-cyclopropyl-N-methoxy-N-methylpiperidine-3-methamide (410 mg, 52%).

Steps 3 to 5: (R)-((R)-1-cyclopropylpiperidin-3-yl)(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5- Methylpyridazin-3-yl)methanol was prepared from (R)-1-cyclopropyl-N-methoxy-N-methylpiperidin-3-methamide in three steps, as in Example 24, steps 4 to As mentioned in 6.

Step 6: To (R)-((R)-1-cyclopropylpiperidin-3-yl)(6-(2-methoxy- To a solution of 4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methanol (50 mg, 1.0 eq) was added BBr ₃ (600 mg, 20 eq) dropwise. The mixture was stirred at 0°C for 1 hour and then at room temperature for a further 1 hour. The reaction was quenched at 0 °C with saturated _aqueous NaHCO solution. The reaction mixture was extracted with a mixed solvent of 5% IPA in DCM (3 x 15 mL). The crude mixture was purified on a silica column to obtain 2-(6-((R)-((R)-1-cyclopropylpiperidin-3-yl)(hydroxy)methyl)-4-methylpyridinium Azin-3-yl)-5-(trifluoromethyl)phenol ( compound 25 ) (40 mg, 84%). ESI-MS (EI ⁺ , m/z): 408.2. Example 26 : Synthesis of 2-(6-( hydroxy ((R)-1- methylpyrrolidin -3- yl ) methyl )-4- methylpyridin -3- yl )-5-( trifluoromethyl ) phenol ( compound 26)

Steps 1 and 2: (R)-3-(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2-carbonyl)pyrrolidine-1-carboxylic acid Tributyl ester ( Int-26-1 ) (188 mg) was prepared as described in Example 24, steps 1 to 4 starting from (R)-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid.

Step 3: To (R)-3-(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methyl in MeOH (5 mL) at 0 °C To a solution of tert-butylfuran-2-carbonyl)pyrrolidine-1-carboxylate ( Int-26-1 ) (180 mg, 1.0 eq) was added NaBH ₄ (8 mg, 0.5 eq). The mixture was stirred at 0 °C for 30 min and quenched with saturated aqueous NaHCO ₃ solution. The mixture was extracted with DCM (2 x 25 mL). The crude mixture was purified on a silica column to obtain (3R)-3-(hydroxy(5-(2-methoxy-4-(trifluoromethyl)phenyl))-4-methylfuran-2-yl ) Methyl)pyrrolidine-1-carboxylic acid tert-butyl ester ( Int-26-2 ) (162 mg, 89%).

Steps 4 to 6: 2-(6-(hydroxy((R)-1-methylpyrrolidin-3-yl)methyl)-4-methylpyridin-3-yl)-5-(trifluoromethyl ( 3R )-3-( hydroxy (5-(2-methoxy-4-(tri) The preparation of tert-butyl fluoromethyl)phenyl)-4-methylfuran-2-yl)methyl)pyrrolidine-1-carboxylate ( Int-26-2 ) was started. ESI-MS (EI ⁺ , m/z): 368.1. Example 27 : Synthesis of 2-(6-((R)-((R)-1,3- dimethylpiperidin -3- yl )( hydroxy ) methyl )-4- methylpyridazin -3- yl )-5-( trifluoromethyl ) phenol ( compound 27A) and 2-(6-((S)-((R)-1,3- dimethylpiperidin -3- yl )( hydroxy ) methyl )-4- methylpyrazin -3- yl )-5-( trifluoromethyl ) phenol ( compound 27B)

(3R)-3-(hydroxy(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2-yl)methyl)-3-methylpiperidine -Tert-butyl-1-carboxylate was prepared as described in Example 26, steps 1 to 3, starting from (R)-1-(tert-butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid. (3R)-3-(Hydroxy(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2-yl)methyl)-3-methylpiper tert-butylpyridine-1-carboxylate was purified on a silica gel column to obtain (R)-3-((R)-hydroxy(5-(2-methoxy-4-(trifluoromethyl)phenyl)) -4-Methylfuran-2-yl)methyl)-3-methylpiperidine-1-carboxylic acid tert-butyl ester ( Int-27-1 ) (30 mg) and (R)-3-((S )-Hydroxy(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2-yl)methyl)-3-methylpiperidine-1-carboxylic acid Tributyl ester ( Int-27-2 ) (41 mg).

2-(6-((R)-((R)-1,3-dimethylpiperidin-3-yl)(hydroxy)methyl)-4-methylpyridazin-3-yl)-5- (Trifluoromethyl)phenol ( Compound 27A ) (23 mg) was obtained from (R)-3-((R)-hydroxy(5-(2- The preparation of tert-butyl methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2-yl)methyl)-3-methylpiperidine-1-carboxylate was started. ESI-MS (EI ⁺ , m/z): 396.0.

2-(6-((S)-((R)-1,3-dimethylpiperidin-3-yl)(hydroxy)methyl)-4-methylpyridazin-3-yl)-5- (Trifluoromethyl)phenol ( Compound 27B ) (19 mg) was obtained from (R)-3-((S)-hydroxy(5-(2- The preparation of tert-butyl methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2-yl)methyl)-3-methylpiperidine-1-carboxylate was started. ESI-MS (EI ⁺ , m/z): 396.0. Example 28 : Synthesis of 2-(6-((1R) -hydroxy ( quinuclidin -3- yl ) methyl )-4- methylpyridazin -3- yl )-5-( trifluoromethyl ) phenol ( Compound 28A) and 2-(6-((1S) -hydroxy ( quinuclidin -3- yl ) methyl )-4- methylpyridazin -3- yl )-5-( trifluoromethyl ) phenol ( Compound 28B)

(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2-yl)(quinuclidin-3-yl)methanol is as in Example 26 Examples 1 to 3 Preparation starts from quinuclidine-3-carboxylic acid as described in . Purify (5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2-yl)(quinuclidin-3-yl)methanol on a silica gel column, Obtain (1R)-(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2-yl)(quinuclidin-3-yl)methanol ( Int- 28-1 ) (40 mg) and (1S)-(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2-yl)(quinuclidine- 3-yl)methanol ( Int-28-2 ) (29 mg).

To a solution of Int-28-1 (40 mg) in THF (2 mL) and water (0.2 mL) was added 4N HCl in dioxane (28 μL, 1.1 eq). The solution was cooled at -15°C for 10 min and solid NBS (24 mg, 1.3 eq) was then added portionwise. The mixture was stirred at -15°C for 30 min, then _{NH2NH2hydrate} (10 eq) _was added dropwise. The resulting mixture was stirred at 0°C for 30 minutes and then at room temperature for 1 hour. The reaction was quenched with saturated NaHCO ₃ and extracted by DCM (2 x 20 mL). The crude mixture was purified on a silica column to obtain (1R)-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(quinone) Ninccyclin-3-yl)methanol (28 mg, 68%), which was treated with BBr ₃ (345 mg, 20 eq) as described in Example 25, step 6, gave 2-(6-((1R)- Hydroxy(quinuclidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol ( Compound 28A ) (18 mg, 66%). ESI-MS (EI ⁺ , m/z): 394.1.

2-(6-((1S)-Hydroxy(quinuclidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol ( Compound 28B ) ( 15 mg) was prepared in a similar manner starting from Int-28-2 . ESI-MS (EI ⁺ , m/z): 394.0. Example 29 : Synthesis of 2-(6-((1- azabicyclo [3.2.1] oct -5- yl )( hydroxy ) methyl )-4- methylpyridazin -3- yl )-5-( tri Fluoromethyl ) phenol ( compound 29)

2-(6-((1-azabicyclo[3.2.1]oct-5-yl)(hydroxy)methyl)-4-methylpyrazin-3-yl)-5-(trifluoromethyl) Phenol ( Compound 29 ) was prepared as described in Example 28 starting from 1-azabicyclo[3.2.1]octane-5-carboxylic acid. ESI-MS (EI ⁺ , m/z): 394.2. Example 30 : Synthesis of (6-(2- methoxy -4-( trifluoromethyl ) phenyl )-5- methylpyridazin -3- yl )(1 -methylazetidine -3- base ) methanol ( compound 30)

3-(Hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)azetidine-1-carboxylic acid Tributyl ester ( Int-30-1 ) was prepared as described in Example 26, steps 1 to 4 starting from 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid.

To a solution of Int-30-1 (78 mg) in DCM (1 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and dissolved in 1,2-dichloroethane. To the solution were added triethylamine (20 mg, 1.1 eq), HCHO (17 mg, 37% in water, 1.2 eq). The mixture was stirred at room temperature for 30 minutes, then NaBH(OAc) ₃ (91 mg, 1.5 eq) was added. Upon completion, the reaction was quenched with saturated aqueous _NaHCO3 solution. The crude mixture was purified on a silica column to obtain (6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methylnitrogen Heterocyclobutan-3-yl)methanol ( compound 30 ) (48 mg, 79%). ESI-MS (EI ⁺ , m/z): 368.2. Example 31 : Synthesis of 2-(6-( hydroxy (1- methylazetidin -3- yl ) methyl )-4- methylpyridazin -3- yl )-5-( trifluoromethyl ) Phenol ( compound 31)

2-(6-(Hydroxy(1-methylazetidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol ( Compound 31 ) is as described in Example 25 step 6 from (6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methylnitrogen The preparation of heterocyclobutan-3-yl)methanol ( compound 30 ) was initiated. ESI-MS (EI ⁺ , m/z): 354.0. Example 32 : Synthesis of 2-(6-( hydroxy (1- methylazepan -3- yl ) methyl )-4- methylpyridazin -3- yl )-5-( trifluoromethyl ) Phenol ( compound 32)

2-(6-(Hydroxy(1-methylazepan-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol ( Compound 32 ) was prepared as described in Example 27 starting from 1-(tert-butoxycarbonyl)azepane-3-carboxylic acid. ESI-MS (EI ⁺ , m/z): 396.1. Example 33 : Synthesis of 2-(6-( hydroxy (2- methyl -2- azabicyclo [2.2.2] oct -4- yl ) methyl )-4- methylpyridazin -3- yl )-5 -( Trifluoromethyl ) phenol ( compound 33)

2-(6-(hydroxy(2-methyl-2-azabicyclo[2.2.2]oct-4-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoro Methyl)phenol ( Compound 33 ) was prepared as described in Example 27 starting from 2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.2]octane-4-carboxylic acid. ESI-MS (EI ⁺ , m/z): 408.2. Example 34 : Synthesis of 2-(6-( hydroxy (8- methyl -8- azabicyclo [3.2.1] oct -2- yl ) methyl )-4- methylpyrazin -3- yl )-5 -( Trifluoromethyl ) phenol ( compound 34)

2-(6-(hydroxy(8-methyl-8-azabicyclo[3.2.1]oct-2-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoro Methyl)phenol ( Compound 34 ) was prepared as described in Example 27 starting from 8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octane-2-carboxylic acid. ESI-MS (EI ⁺ , m/z): 408.1. Example 35 : Synthesis of 2-(6-( hydroxy (3- methyl -3- azabicyclo [3.1.1] hept -1- yl ) methyl )-4- methylpyridazin -3- yl )-5 -( Trifluoromethyl ) phenol ( compound 35)

2-(6-(hydroxy(3-methyl-3-azabicyclo[3.1.1]hept-1-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoro Methyl)phenol ( Compound 35 ) was prepared as described in Example 27 starting from 3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.1]heptane-1-carboxylic acid. ESI-MS (EI ⁺ , m/z): 394.2. Example 36 : Synthesis of 2-(6-( hydroxy (2- methyl -2- azabicyclo [2.2.1] hept -6- yl ) methyl )-4- methylpyridazin -3- yl )-5 -( Trifluoromethyl ) phenol ( compound 36)

2-(6-(Hydroxy(2-methyl-2-azabicyclo[2.2.1]hept-6-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoro Methyl)phenol ( Compound 36 ) was prepared as described in Example 27 starting from 2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-6-carboxylic acid. ESI-MS (EI ⁺ , m/z): 394.0. Example 37 : Synthesis of (6R,8aS)-6-((R) -hydroxy (6-(2- hydroxy- 4-( trifluoromethyl ) phenyl )-5- methylpyridazin -3- yl ) methyl Hexahydroinazine - 3(2H) -one ( compound 37 )

6-(Hydroxy(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)hexahydroindolin-3(2H)-one( (Mixture of trans isomers) ( Compound 37 ) was prepared as described in Example 27 starting from 3-side oxyswaindoline-6-carboxylic acid (Mixture of trans isomers). ESI-MS (EI ⁺ , m/z): 422.2. Example 37 : Synthesis of (6R,8aS)-6-((R) -hydroxy (6-(2- hydroxy- 4-( trifluoromethyl ) phenyl )-5- methylpyridazin -3- yl ) methyl Hexahydroindolin - 3(2H) -one ( mixture of trans isomers ) ( Compound 37)

6-(Hydroxy(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)hexahydroindolin-3(2H)-one( (Mixture of trans isomers) ( Compound 37 ) was prepared as described in Example 27 starting from 3-side oxyswaindoline-6-carboxylic acid (Mixture of trans isomers). ESI-MS (EI ⁺ , m/z): 422.2. Example 38 : Synthesis of 2-(6-( hydroxy ( swainlin -6- yl ) methyl )-4- methylpyridazin- 3- yl )-5-( trifluoromethyl ) phenol ( trans-iso mixture of conformations ) ( compound 38)

To 6-(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4- from Example 37 in anhydrous THF (5 mL) at ₀ °C under N To a solution of methylfuran-2-carbonyl)hexahydroindolin-3(2H)-one (mixture of trans isomers) (32 mg, 1.0 eq) was added LAH (1M in ether, 0.76 mL, 10 eq). The resulting mixture was heated at 55°C for 15 hours. The reaction was quenched with IN NaOH and extracted with DCM (3 x 20 mL) and concentrated in vacuo to give (5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran -2-yl)(swainlin-6-yl)methanol (24 mg, 77%).

2-(6-(Hydroxy(swainlin-6-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (mixture of trans isomers ) ( Compound 38 ) is as described in Step 6 of Example 24 and Step 6 of Example 25 from (5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2- The preparation of (squahydrin-6-yl)methanol (a mixture of trans isomers) was started. ESI-MS (EI ⁺ , m/z): 408.4. Example 39 : Synthesis of 2-(6-( hydroxy (1- methylpiperidin -2- yl ) methyl )-4- methylpyridazin -3- yl )-5-( trifluoromethyl ) phenol ( compound 39)

To a solution of 3,6-dichloro-4-methylpyridazine (820 mg, 5 mmol) and 2-pyridylacetonitrile (610 mg, 5.2 mmol) in anhydrous DMA (8 mL) at 0°C Add NaH (420 mg, 10.5 mmol, 60%) in portions. After 30 min at 0°C, m-CPBA (1.2 g, 5 mmol, 72% purity) was added portionwise to the solution over 2 min at 0°C. The reaction mixture was diluted with EtOAc (20 mL) and stirred at 0 °C for an additional 10 min. Saturated aqueous NaHCO ₃ (20 mL) was added to the solution and the mixture was stirred for 10 min at 0 °C. The mixture was diluted with water (20 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (3 x 30 mL), saturated _NaHCO3 (50 mL), brine (50 mL) and _dried over _Na2SO4 . The solvent was concentrated and the solid was sonicated in EtOAc (10 mL) and collected by filtration. The solid was further purified on a silica column to obtain (6-chloro-5-methylpyridazin-3-yl)(pyridin-2-yl)methanone ( Int-39-1 ) (298 mg).

To (6-chloro-5-methylpyridazin-3-yl)(pyridin-2-yl)methanone ( Int-39- 1 ) Add NaBH ₄ (8 mg, 0.5 eq) to the solution (100 mg, 1.0 eq). The resulting mixture was stirred at 0°C for 15 minutes. The reaction was quenched with saturated aqueous _NaHCO3 and then extracted with ethyl acetate to give (6-chloro-5-methylpyridazin-3-yl)(pyridin-2-yl)methanol (100 mg).

(6-Chloro-5-methylpyridazin-3-yl)(pyridin-2-yl)methanol (100 mg, 1.0 eq) in dioxane (5 mL) and water (2 mL), of (2-Hydroxy-4-(trifluoromethyl)phenyl)boronic acid (115 mg, 1.3 eq), PdCl ₂ (dppf) (28 mg, 0.1 eq) and Na ₂ CO ₃ (100 mg, 2.0 eq) The mixture was heated at 100°C for 8 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water, brine and concentrated in vacuo. The crude mixture was purified on a silica column to obtain 2-(6-(hydroxy(pyridin-2-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (102 mg).

To 2-(6-(hydroxy(pyridin-2-yl)methyl)-4-methylpyridazin-3-yl)-5-(tris) in MeOH (20 mL) and water (0.2 mL) To a solution of fluoromethyl)phenol (100 mg, 1.0 eq) was added PtO ₂ (50 mg, 0.8 eq) and (Boc) ₂ O (78 mg, 1.3 eq). The mixture was degassed by bubbling _N2 gas for 20 minutes, and then hydrogenated under _H2 (balloon) at room temperature for 15 hours. The catalyst was removed by filtration and the solvent was concentrated in vacuo. The crude mixture was purified on a silica column to obtain 3-(hydroxy(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-2-yl)methyl)piper Tert-butylpyridine-1-carboxylate (42 mg).

To 2-(hydroxy(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)piperidine in DCM (1 mL) -To a solution of tert-butyl-1-carboxylate (42 mg) was added HCl (4N, 1 mL). The mixture was stirred at room temperature for 25 minutes. The mixture was concentrated in vacuo to give 2-(6-(hydroxy(piperidin-2-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (35 mg, HCl salt).

To 2-(6-(hydroxy(piperidin-2-yl)methyl)-4-methylpyridazine-3 in 1,2-dichloroethane (5 mL) and MeOH (0.5 mL) -To a solution of -5-(trifluoromethyl)phenol HCl salt (35 mg, 1.0 eq), triethylamine (1.0 eq), HCHO (8.5 mg, 37% in water, 1.2 eq) and 1 Drops of AcOH. The mixture was stirred at room temperature for 15 min and NaBH(OAc) ₃ (29 mg, 1.5 eq) was added. The resulting mixture was stirred at room temperature for 30 minutes, quenched with saturated aqueous _NaHCO3 solution and stirred at room temperature for 10 minutes. The mixture was extracted with DCM (4 x 25 mL). The combined organic extracts were concentrated and the residue was purified on a silica gel column to obtain 2-(6-(hydroxy(1-methylpiperidin-2-yl)methyl)-4-methyl as a white solid Pyrazin-3-yl)-5-(trifluoromethyl)phenol ( compound 39 ) (22 mg). ESI-MS (EI ⁺ , m/z): 382.2. Example 40 : Synthesis of 2-(6-((R) -hydroxy ((R) -piperidin - 3- yl ) methyl )-4- methylpyridazin -3- yl )-5-( trifluoromethyl ) phenol ( compound 40)

To a solution of compound 17-1B (55 mg) in DCM (0.5 mL) was added 4N HCl in dioxane (1 mL). The mixture was stirred at room temperature for 30 minutes and concentrated in vacuo to give 2-(6-((R)-hydroxy((R)-piperidin-3-yl)methyl)-4-methylpyridazine-3 -yl)-5-(trifluoromethyl)phenol ( compound 40 ) (46 mg, 98%). ESI-MS (EI ⁺ , m/z): 368.1. Example 41 : Synthesis of 2-(6-((R) -hydroxy ((R)-1- isopropylpiperidin -3- yl ) methyl )-4- methylpyridazin -3- yl )-5- ( Trifluoromethyl ) phenol ( compound 41)

2-(6-((R)-Hydroxy((R)-piperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol ( Compound 40 ) (20 mg, 1.0 eq) HCl salt and anhydrous acetone (9 mg, 3 eq) were combined in anhydrous 1,2-dichloroethane (2 mL). To the mixture was added TEA (6 mg, 1.2 eq) and one drop of AcOH (approximately 5 mg). The mixture was stirred at room temperature for 5 hours and NaBH(OAc) ₃ (52 mg, 5.0 eq) was added. The resulting mixture was stirred at room temperature for 1 hour and then heated at 50°C overnight. The reaction mixture was cooled and quenched with saturated _NaHCO3 . The residue was purified on a silica column to obtain 2-(6-((R)-hydroxy((R)-1-isopropylpiperidin-3-yl)methyl)-4-methylpyridazine- 3-yl)-5-(trifluoromethyl)phenol ( compound 41 ) (5 mg, 26%). ESI-MS (EI ⁺ , m/z): 410.2. Example 42 : Synthesis of 4- fluoro -2-(6-( hydroxy ((R)-1- methylpiperidin -3- yl ) methyl )-4- methylpyridazin -3- yl )-5-( Trifluoromethyl ) phenol ( compound 42)

4-fluoro-2-(6-(hydroxy((R)-1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl ) Phenol ( Compound 42 ) was prepared as described in Example 24, Steps 1 to 7 using (5-fluoro-2-methoxy-4-(trifluoromethyl)phenyl)boronic acid in Step 2 and Example 25, Step 6 Prepared as described in . ESI-MS (EI ⁺ , m/z): 400.1. Example 43 : Synthesis of 2-(4-((R) -hydroxy ((R)-1- methylpiperidin -3- yl ) methyl )-6,7- dihydro -5H- cyclopenta [d] Pyrazin- 1- yl )-5-( trifluoromethyl ) phenol (±) mixture ( compound 43A ) and 2-(4-((R/S) -hydroxy ((R/S)-1- methyl) Piperidin -3- yl ) methyl )-6,7- dihydro -5H- cyclopenta [d] pyridazin -1- yl )-5-( trifluoromethyl ) phenol (±) mixture ( Compound 43B )

To a solution of 3,6-dichloro-1,2,4,5-tetrazine (5.0 g, 33.1 mmol) in dichloromethane (50 mL) at 0 °C was added dropwise 1- (Cyclopent-2-en-1-yl)pyrrolidine (4.83 mL, 33.1 mmol). After an additional 15 minutes, the reaction was quenched by adding 30 mL of 10% aqueous citric acid (50 mL) and water (30 mL). The reaction was removed from the ice bath and stirred vigorously for 5 minutes. The reaction mixture was then extracted with 3 × 30 _{mL CH2Cl2} . The combined organic layers were washed with brine (30 mL), dried over _MgSO4 , filtered and concentrated to dryness. Purification by column chromatography gave 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (3.4 g, 54%) as a white solid. ¹ H NMR (400 MHz, chloroform-d): δ 3.10 (t, J = 7.8 Hz, 4H), 2.36 - 2.14 (m, 2H).

To a solution of 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (3.4 g, 17.99 mmol) in DMF (200 mL) was added tributyl(ethylene (5.7 g, 17.99 mmol, 1.0 eq.) and PdCl ₂ (PPh ₃ ) ₂ (1.26 g, 10.37 mmol, 0.2 eq.). The resulting mixture was stirred at room temperature under _N2 atmosphere for 48 hours. The reaction solution was diluted with water, extracted with EtOAc, dried over Na ₂ SO ₄ , filtered and purified by column chromatography to obtain 1-chloro-4-vinyl-6,7-dihydro-5H as a white solid. -Cyclopenta[d]pyridazine (1.78 g, 54%). ¹ H NMR (400 MHz, chloroform-d): δ 6.94 (dd, J = 11.2, 11.6 Hz, 1H), 6.38 (d, J = 17.6 Hz, 1H), 5.71 (d, J = 11.2 Hz, 1H) , 3.08 (dt, J = 32.8, 7.6 Hz, 4H), 2.23 (q, J = 7.6 Hz, 2H).

To 1-chloro-4-vinyl-6,7-dihydro-5H-cyclopenta[d]pyridazine (1.78 g, 9.85) in 3:1 dioxane/H ₂ O (24 mL) mmol), add (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (3.25 g, 14.78 mmol, 1.5 eq.), Na ₂ CO ₃ (2.09 g, 19.71 mmol, 2.0 eq. .) and Pd(dppf)Cl ₂ (721 mg, 0.99 mmol, 0.1 eq.). The resulting mixture was stirred at 100°C for 1 hour. The reaction solution was diluted with water, extracted with EtOAc, dried over Na ₂ SO ₄ , filtered and purified by column chromatography to obtain 1-(2-methoxy-4-(trifluoromethyl) as a yellow solid Phenyl)-4-vinyl-6,7-dihydro-5H-cyclopenta[d]pyridazine (1.87 g, 59%). ESI-MS (EI ⁺ ): m/z 321.10.

To 1-(2-methoxy-4-(trifluoromethyl)phenyl)-4-vinyl-6,7-dihydro- in 1:1 ACN/H ₂ O (20 mL) To the solution of 5H-cyclopenta[d]pyridazine (1.87 g, 5.84 mmol, 1 eq), NaIO ₄ (6.24 g, 29.19 mmol, 5 eq), OsO ₄ (0.1 mg, 0.58 mmol, 0.1 eq) and NMO (3.42 g, 29.19 mmol, 5 eq). The resulting mixture was stirred at 0°C for 1 hour. The reaction solution was diluted with EtOAc and _H2O , and the organic layer was dried ( _Na2SO4 ), filtered and _concentrated . The residue was purified by column chromatography to obtain 4-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta as a yellow solid [d]pyridazine-1-carbaldehyde (180 mg, 10%). ¹ H NMR (400 MHz, chloroform-d): δ 10.52 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.25 (s, 1H) , 3.88 (s, 3H), 3.42 (t, J = 7.6 Hz, 2H), 2.88 (t, J = 7.6Hz, 2H), 2.22 - 2.13 (m, 2H).

To a solution of 1-methylpiperidin-2-one (180 mg, 0.67 mmol, 1.2 eq) in THF (4 mL) was added LDA (698 mL, 2M, 1.4 mmol, 2.5 eq). After 1 hour, 4-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazine-1-carbaldehyde (180 mg, 0.558 mmol, 1 eq) and the reaction was stirred at -78°C for an additional 1 hour. The reaction solution was diluted with EtOAc and _H2O , and the organic layer was dried ( _Na2SO4 ), filtered and _concentrated . Purification by column chromatography and then preparative TLC (1:20 MeOH/DCM) three times gave (S/R)-3-((R/S)-hydroxy(4-(2-methoxy- 4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)methyl)-1-methylpiperidin-2-one (± ) mixture ( Int-43A-1 ) (80 mg, 33%) and (R/S)-3-((R/S)-hydroxy(4-(2-methoxy-4-(trifluoromethyl )Phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)methyl)-1-methylpiperidin-2-one(±) mixture ( Int-43B- 1 ) (80 mg, 33%).

To a solution of Int-43A-1 (80 mg, 0.18 mmol) in THF (1 mL) under _N2 atmosphere at 0 °C was added _BH3.DMS (140 mg, 1.84 mmoL, 10.0 eq) . The reaction mixture was heated to 55°C for 2 hours and then cooled to 0°C and AcOH (0.5 mL) added. The resulting mixture was stirred at 55°C for 1 hour. The reaction solution was diluted with MeOH and then concentrated in vacuo to give (R)-(4-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro as a yellow oil -5H-cyclopenta[d]pyridazin-1-yl)((R)-1-methylpiperidin-3-yl)methanol(±) mixture ( Int-43A-2 ) (80 mg, crude ). ESI-MS (EI ⁺ ): m/z 422.15.

To a solution of Int-43A-2 (80 mg) in DCM (1 mL) at 0 °C under _N2 was added _BBr3 (3 mL). The resulting mixture was stirred at 40°C for 2 hours. The reaction solution was diluted with MeOH, concentrated in vacuo and purified by preparative HPLC to give 2-(4-((R)-hydroxy((R)-1-methylpiperidin-3-yl) as a white solid )-methyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (±) mixture ( Compound 43A ) (9.5 mg, 12 %). ESI-MS (EI ⁺ ): m/z 408.10. ¹ H NMR (400 MHz, methanol-d ₄ ): δ 8.52 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H ), 4.89 (s, 1H), 3.78 (d, J = 12.2 Hz, 1H), 3.43 (d, J = 12.4 Hz, 1H), 3.30 - 3.17 (m, 2H), 3.11 (t, J = 7.6 Hz , 2H), 3.05 - 2.90 (m, 2H), 2.89 (s, 3H), 2.65 - 2.52 (m, 1H), 2.19 (p, J = 7.6 Hz, 2H), 1.97 (dq, J = 14.6, 3.6 Hz, 1H), 1.85 - 1.71 (m, 1H), 1.58 - 1.40 (m, 2H).

To a solution of Int-43 B -1 (80 mg, 0.18 mmol) in THF (1 mL) under _N2 atmosphere at 0 °C was added _BH3.DMS (140 mg, 1.84 mmoL, 10.0 eq ). The reaction mixture was heated to 55°C for 2 hours and then cooled to 0°C and AcOH (0.5 mL) added. The resulting mixture was stirred at 55°C for 1 hour. The reaction solution was diluted with MeOH and then concentrated in vacuo to give (R)-(4-(2-methoxy-4-(trifluoromethyl)phenyl)-6,7-dihydro as a yellow oil -5H-cyclopenta[d]pyridazin-1-yl)((R)-1-methylpiperidin-3-yl)methanol(±) mixture ( Int-43B-2 ) (60 mg, crude ). ESI-MS (EI ⁺ ): m/z 422.15.

To a solution of Int-43 B -2 (60 mg) in DCM (1 mL) was added _BBr3 (3 mL) at 0 °C under _N2 . The resulting mixture was stirred at 40°C for 2 hours. The reaction solution was diluted with MeOH, concentrated in vacuo and purified by preparative HPLC to obtain 2-(4-((R/S)-hydroxy((R/S)-1-methylpiperidine) as a white solid -3-yl)methyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol (±) mixture ( Compound 43B ) ( 9.2 mg, 16%). ESI-MS (EI ⁺ ): m/z 408.10. ¹ H NMR (400 MHz, methanol-d ₄ ): δ 8.52 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.32 - 7.29 (m, 2H), 4.96 (d, J = 6.4 Hz , 1H), 3.45 (d, J = 11.6 Hz, 1H), 3.34 - 3.20 (m, 5H), 3.15 - 3.11 (m, 2H), 3.00 - 2.84 (m, 2H), 2.60 - 2.56 (m, 1H ), 2.25 - 2.17 (m, 2H), 2.07 - 2.04 (m, 2H), 1.87 - 1.77 (m, 1H), 1.57 - 1.48 (m, 1H). Example 44 : Synthesis of 2-(4-((R) -hydroxy ((R)-1- methylpiperidin -3- yl ) methyl )-6,7- dihydro -5H- cyclopenta [d] Pyrazin -1- yl )-5-( trifluoromethyl ) phenol (±) mixture ( Compound 44 )

To 1,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyridazine (10.5 g, 55.54 mmol) in THF (100 mL) at 0 °C under _N2 To a mixture of 2-(3-pyridyl)acetonitrile (6.56 g, 55.54 mmol, 5.97 mL), NaH (4.67 g, 116.64 mmol, 60% purity) was added portionwise. The mixture was stirred at 0°C for 1 hour. m-CPBA (17.57 g, 61.10 mmol, 60% purity) was added to the solution in portions over 10 min at 0°C. The mixture was stirred at 0°C for 0.5 hours. LCMS showed the reaction was complete. The reaction was quenched at 0°C by adding saturated _NaHCO3 (100 mL) and the mixture was stirred for 10 min. The mixture was diluted with water (200 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine ₍ 250 mL), dried over _Na2SO4 and concentrated to give a residue. The residue was triturated with MTBE (50 mL) at 20°C for 0.5 hours and filtered to obtain (4-chloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl) as a brown solid. (Pyridin-3-yl)methanone (7.28 g, 50%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.08 (d, J = 1.6 Hz, 1H), 8.85 (dd, J = 2.0, 5.2 Hz, 1H), 8.32 (td, J = 2.0, 8.0 Hz , 1H), 7.66 - 7.57 (m, 1H), 3.32 (t, J = 7.6 Hz, 2H), 3.09 (t, J = 7.6 Hz, 2H), 2.17 (quin, J = 7.6 Hz, 2H).

To (4-chloro-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)(pyridin- To a mixture of 3-yl)methanone (7.2 g, 27.73 mmol) was added NaBH ₄ (1.05 g, 27.73 mmol) portionwise. The mixture was stirred at 0°C for 0.5 hours. The reaction was quenched with saturated _NaHCO3 (100 mL) at 0°C and extracted with EA (80 mL × 3). The organic layer was washed with brine (100 mL), dried _{over Na2SO4} and concentrated to give a residue. The residue was purified by column chromatography to obtain (4-chloro-6,7-dihydro-5H-cyclopenta[d]pyridin-1-yl)(pyridin-3-yl) as a colorless oil ) methanol (5.1 g, 70%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.58 (d, J = 2.0 Hz, 1H), 8.47 (dd, J = 1.6, 5.2 Hz, 1H), 7.80 - 7.73 (m, 1H), 7.37 (dd, J = 4.8, 8.0 Hz, 1H), 6.55 (d, J = 5.2 Hz, 1H), 6.14 (d, J = 4.4 Hz, 1H), 3.23 - 3.10 (m, 1H), 2.93 (t, J = 7.6 Hz, 2H), 2.85 - 2.72 (m, 1H), 2.13 - 1.94 (m, 2H).

To (4-chloro-6,7-dihydro-5H-cyclopenta[d]pyridazine-1- in dioxane (40 mL) and _H2O (20 mL) under _N A mixture of (pyridin-3-yl)methanol (5.1 g, 19.49 mmol) and (2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)boronic acid (6.33 g, 25.33 mmol) Na ₂ CO ₃ (5.16 g, 48.72 mmol) and Pd(dppf)Cl ₂ (713 mg, 974.37 μmol) were added. The mixture was stirred at 105°C for 12 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with brine ₍ 100 mL), dried over _Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography to obtain (4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dihydro- as a yellow solid) 5H-Cyclopenta[d]pyridazin-1-yl)(pyridin-3-yl)methanol (4.2 g, 50%). ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.65 (d, J = 2.0 Hz, 1H), 8.48 (dd, J = 1.6, 4.4 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H ), 7.61 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.39 (dd, J = 4.8, 7.6 Hz, 1H), 6.52 (d , J = 4.4 Hz, 1H), 6.22 (d, J = 4.4 Hz, 1H), 5.30 - 5.24 (m, 2H), 3.26 (s, 3H), 3.22 - 3.13 (m, 1H), 2.87 - 2.78 ( m, 1H), 2.75 (dt, J = 3.6, 7.6 Hz, 2H), 2.04 - 1.89 (m, 2H).

To (4-(2-(methoxymethoxy)-4-(trifluoromethyl)benzene) in MeOH (500 mL) and _H2O (5 mL) was added at ₂₀ °C under N PtO ₂ (1.77 g, 7.79 mmol) and Boc ₂ O (2.76 g, 12.66 mmol, 2.91 mL). The suspension was degassed under vacuum and purged several times with _H2 . The mixture was stirred under _H2 (15 psi) at 20°C for 12 hours. The mixture was filtered through celite and the filtrate was concentrated to obtain 3-(hydroxy(4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7) as a yellow solid -Dihydro-5H-cyclopenta[d]pyridazin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (5.4 g, 94%). ¹ H NMR (400 MHz, chloroform-d): δ 7.59 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 5.20 - 5.15 (m, 2H), 4.93 - 4.79 (m, 1H), 3.46 - 3.38 (m, 3H), 3.15 - 3.01 (m, 2H), 3.00 - 2.91 (m, 2H), 2.89 (dd, J = 5.2, 8.8 Hz, 2H), 2.21 (td, J = 6.8, 13.6 Hz, 1H), 2.12 (ddd, J = 4.8, 8.4, 16.4 Hz, 2H), 1.79 - 1.65 (m, 2H), 1.60 (s, 2H), 1.48 - 1.40 (m, 9H).

To 3-(hydroxy(4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl))-6,7-dihydro in DCM (60 mL) at 0 °C To a mixture of -5H-cyclopenta[d]pyridazin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (5.3 g, 9.86 mmol), DMP (4.60 g, 10.85 mmol, 3.36 mL). The mixture was stirred at 20°C for 0.5 hours. LCMS showed the reaction was complete. The reaction was quenched with saturated _NaHCO3 (100 mL) and extracted with DCM (80 mL × 3). The organic layer was washed with brine (100 mL), dried _{over Na2SO4} and concentrated to give a residue. The residue was purified by column chromatography to obtain 3-(4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-di as a yellow solid Hydro-5H-cyclopenta[d]pyridazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (3.18 g, 60%). ¹ H NMR (400 MHz, chloroform-d): δ 7.63 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H), 5.19 (s, 2H) , 4.30 (s, 1H), 4.19 - 4.09 (m, 1H), 3.42 (s, 3H), 3.42 - 3.37 (m, 2H), 3.36 - 3.26 (m, 1H), 2.90 (t, J = 7.6 Hz , 2H), 2.29 - 2.21 (m, 1H), 2.14 (quin, J = 7.6 Hz, 2H), 1.83 (dd, J = 4.4, 8.8 Hz, 1H), 1.76 - 1.56 (m, 4H), 1.47 - 1.40 (m, 9H).

3-(4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazine-1-carbonyl ) Piperidine-1-carboxylic acid tert-butyl ester (3.18 g, 5.94 mmol) was separated and purified by SFC to obtain (R)-3-(4-(2-(methoxymethoxy)-4) as a yellow solid -(Trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 38%) . ¹ H NMR (400 MHz, chloroform-d): δ 7.63 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 5.19 (s, 2H) , 4.30 (s, 1H), 4.14 (dd, J = 4.0, 13.2 Hz, 1H), 4.07 - 3.82 (m, 1H), 3.42 (s, 3H), 3.40 (s, 1H), 3.32 (d, J = 6.0 Hz, 1H), 3.09 - 2.94 (m, 1H), 2.90 (t, J = 8.0 Hz, 2H), 2.30 - 2.21 (m, 1H), 2.14 (quin, J = 7.6 Hz, 2H), 1.83 (dd, J = 4.8, 8.8 Hz, 1H), 1.69 (s, 3H), 1.51 - 1.37 (m, 9H).

To (R)-3-(4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6 in DMF (5 mL) under _N atmosphere, To a solution of 7-dihydro-5H-cyclopenta[d]pyridazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 933.61 μmol) was added (1Z,5Z)-cyclooctane- 1,5-diene; rhodium(1+); tetrafluoroborate (38 mg, 93.36 μmol) and (S)-(+)-DTBMSEGPHOS (132 mg, 112.03 μmol). The suspension was degassed and purged with H ₃ times. The mixture was stirred under _H2 (3 MPa) at 30°C for 12 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (5 mL × 3). The organic layer was washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated to give (R)-3-((R)-hydroxy(4-(2-(methoxymethoxy)) as a yellow oil -4-(Trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyridazin-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 99.6%). ¹ H NMR (400 MHz, chloroform-d): δ 7.58 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 5.18 (s, 2H) , 4.84 (s, 1H), 3.97 - 3.77 (m, 2H), 3.43 (s, 3H), 3.14 - 3.05 (m, 2H), 2.95 - 2.90 (m, 1H), 2.27 - 2.19 (m, 1H) , 2.17 - 2.08 (m, 1H), 1.80 - 1.69 (m, 2H), 1.46 (d, J = 1.6 Hz, 2H), 1.43 (s, 9H).

To (R)-3-((R)-hydroxy(4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl) in DCM (1 mL) at 20 °C 1, 4-Dioxane; hydrochloride (1 mL). The mixture was stirred at 20°C for 0.5 hours. The solvent was removed in vacuo to give the intermediate viscous solid. The solid was dissolved in MeOH (2 mL) and 1,2-dichloroethane (10 mL). Then TEA (153 mg, 1.51 mmol), formaldehyde (112 mg, 1.38 mmol) were added to the mixture. The mixture was stirred at 20°C for 15 minutes, then NaBH(OAc) ₃ (438 mg, 2.06 mmol) was added portionwise and the mixture was stirred at 20°C for 2 hours. LCMS showed the reaction was complete. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC (neutral conditions) to obtain 2-(4-((R)-hydroxy((R)-1-methylpiperidin-3-yl)methyl) as a white solid -6,7-Dihydro-5H-cyclopenta[d]pyridazin-1-yl)-5-(trifluoromethyl)phenol ( Compound 44 ) (33 mg, 6%). LCMS (ESI ⁺ ): m/z 408.1 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol- d ₄ ): δ 7.68 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.24 (s, 1H), 4.77 (d, J = 8.8 Hz, 1H ), 3.38 - 3.33 (m, 1H), 3.27 (s, 1H), 3.20 (t, J = 7.6 Hz, 1H), 3.10 (t, J = 7.6 Hz, 2H), 2.90 (d, J = 11.6 Hz , 1H), 2.39 (s, 3H), 2.36 - 2.25 (m, 1H), 2.18 (quin, J = 7.6 Hz, 2H), 2.12 - 2.04 (m, 2H), 1.71 (d, J = 13.2 Hz, 1H), 1.63 - 1.49 (m, 1H), 1.36 - 1.22 (m, 1H), 1.17 - 1.03 (m, 1H). Example 45 : Synthesis of 2-(6-((R)-((R)-1- ethylpiperidin -3- yl )( hydroxy ) methyl )-4- methylpyridazin -3- yl )-5 -( Trifluoromethyl ) phenol ( compound 45)

2-(6-((R)-((R)-1-ethylpiperidin-3-yl)(hydroxy)methyl)-4-methylpyridazin-3-yl)-5-(trifluoro Methyl)phenol ( Compound 45 ) was prepared as described in Example 17 from (R)-3-((R)-hydroxy(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5- Methylpyridazin-3-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester ( compound 17-1B ) was prepared. ESI-MS (EI ⁺ , m/z): 396.2. Example 46 : Human Monocyte IL-1b Analysis

Serially diluted test compounds were incubated with 200 mL of fresh human whole blood for 0.5 h. Cells were stimulated with 100 ng/mL lipopolysaccharide (LPS) for 3.5 hours at 37°C, followed by an additional 45 minutes with 5 mM ATP. The IL-1b concentration in the supernatant was determined using a commercially available ELISA kit. Negative controls are wells with no stimulation, while positive controls are wells with stimulation but only DMSO without added compound. After background subtraction, compound-treated wells were then normalized to the positive control for _IC50 calculations.

_IC50 values are shown in the table below. compound IL-1b (IC ₅₀ ) compound IL-1b (IC ₅₀ ) compound IL-1b (IC ₅₀ ) compound IL-1b (IC ₅₀ ) 1 B 1A B 1B A 2 B 3 A 4 C 5 A 6 B 7 A 8 A 9 A 10 C 11 A 12 B 13 B 14 A 15 A 16 A 17A A 17B A 17C A 17D B 18 A 19 A 20 A twenty one C twenty two A twenty three C twenty four A 25 A 26 A 27A B 27B C 28A A 28B B 29 B 30 C 31 A 32 A 33 B 34 A 35 B 36 A 37 B 38 B 39 A 40 A 41 A 42 A 43A A 43B B 44 A A: IC ₅₀ ＜ 500 nM; B: 500 nM ＜ IC ₅₀ ＜ 3 µM; C: 3 µM ＜ IC ₅₀ ＜ 10 µM

The examples and embodiments described herein are for illustrative purposes only and in some embodiments various modifications or variations are intended to be included within the purview of the invention and the scope of the appended claims.

Claims (79)

A compound of formula (I') or a pharmaceutically acceptable salt or solvate thereof: Formula (I'); where: L is -C(R _9a )(R _9b )-, -C(O)- or -C(=N-OR ₁₆ )-; R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 ring Alkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O )OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ ) (R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O ) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ),- CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally undergo a , two or three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N (R ₁₀ ) (R ₁₁ ); or R ₁ and R ₂ combine to form a 4-, 5-, or 6-membered cycloalkyl ring; a 4-, 5-, or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; the 4-, 5- or 6-membered heterocycloalkyl ring; the 5- or 6-membered heteroaryl ring; or the benzene ring is optionally modified by one or two One or three R ₁₄ groups are substituted; or R ₂ and R ₃ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or a 6-membered heteroaryl ring; or a benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered Heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; or R ₃ and R ₄ combined to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5 - or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6- A membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; or R ₄ and R ₅ are combined to form 4-, 5- or a 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, wherein the 4-, 5- or 6-membered Cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; R ₆ for R _6a is selected from hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl, wherein C _1-6 alkyl and C _3-6 cycloalkyl are optionally separated by one, two or three R ₁₄ groups Substitution; or R _6a and R ₁₅ together form a bridge of -CH ₂ - or -CH ₂ CH ₂ -; R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 hetero Aryl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _{The 1-9} heteroaryl group is optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) group substitution; or R ₇ and R ₈ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6- Membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or the benzene ring is optionally substituted by one, two or three R ₁₄ groups; R _9a and R _9b are each independently selected from hydrogen, halogen, -OH, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy; each R ₁₀ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3 -6} cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne base, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, optionally with one, two or three selected from halogen, C _{1- 6} alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl The radical is substituted; each R ₁₁ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₂ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 Haloalkyl; each R ₁₃ is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, including C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycle Alkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl group substitutions; each R ₁₄ is independently selected from halogen, - CN, C _1-6 alkyl, C _1-6 haloalkyl _{, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl , C 6 -10} aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ ) (R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ) , -C(O)C(O) N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S (=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally modified by one, two or three selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) group substitution; each R ₁₅ is independently selected from halogen, side oxygen group, -CN, C _1-6 alkyl, C _1-6 haloalkyl, _{C 2-6 alkenyl, C 2-6 alkynyl} , C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aromatic group, C _1-9 heteroaryl group, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , - C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O )(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3 -6} cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally have one, two or three selected from halogen, -CN, C _1-6 Alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N (R ₁₀ ) (R ₁₁ ) group substitution; or two R ₁₅ together form -CH ₂ - or -CH ₂ CH ₂ - bridge; R ₁₆ is selected from hydrogen and C _1-6 alkyl; and n is 0, 1, 2, 3 or 4. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: Formula (I); where: L is -C(R _9a )(R _9b )-, -C(O)- or -C(=N-OR ₁₆ )-; R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl Base, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O) OR ₁₀ 、-OC(O)N(R ₁₀ )(R ₁₁ )、-N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ )、-N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )( R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally replaced by one, Two or three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ); or R ₁ and R ₂ combine to form a 4-, 5-, or 6-membered cycloalkyl ring; a 4-, 5-, or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, where The 4-, 5- or 6-membered cycloalkyl ring; the 4-, 5- or 6-membered heterocycloalkyl ring; the 5- or 6-membered heteroaryl ring; or the benzene ring is optionally separated by one or two Or three R ₁₄ groups are substituted; or R ₂ and R ₃ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5-or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered hetero Aryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; or R ₃ and R ₄ combined to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or a 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered Heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or phenyl ring optionally substituted with one, two or three R ₁₄ groups; or R ₄ and R ₅ combined to form 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered ring Alkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; R ₆ for or ; R _6a is selected from hydrogen and C _1-6 alkyl optionally substituted by one, two or three R ₁₄ groups; R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _{1- 6} alkyl, C _1-6 haloalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _{C 2-9 heterocycloalkyl} , C _6-10 aryl and C _1-9 heteroaryl, including C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, _{C 3-6 cycloalkyl, C 2-9 heterocycloalkyl ,} C _{6- 10} aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N( R ₁₀ ) (R ₁₁ ) is substituted with a group; or R ₇ and R ₈ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6 -membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; R _9a and R _9b are each independently selected from hydrogen, halogen, -OH, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy; each R ₁₀ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from the group consisting of one, two or three Halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl group substitution; each R ₁₁ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₂ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₃ is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 hetero Cycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one, two or three selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl , C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl groups are substituted; each R ₁₄ is independently Selected from halogen, -CN, C _1-6 alkyl, C _{1-6 haloalkyl, C 2-6 alkenyl} , C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycle Alkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O) N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S (O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C( O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from halogen by one, two or three , -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N (R ₁₀ ) (R ₁₁ ) group substitution; each R ₁₅ is independently selected from halogen, side oxygen group , -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C( O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )- , S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally have one, two or three selected from halogen, -CN , C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N (R ₁₀ ) (R ₁₁ ) group substitution; R ₁₆ is selected from hydrogen and C _1-6 alkyl; and n is 0, 1, 2, 3 or 4. Such as the compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . Such as the compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is a C _1-6 alkyl group optionally substituted by one, two or three R ₁₄ groups . The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is an unsubstituted C _1-6 alkyl group. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is -CH ₃ . Such as the compound of claim 1, or its pharmaceutically acceptable salt or solvate, wherein R ₆ is . Such as the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. Such as the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is selected from: The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl , C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _{1- 9} heteroaryl, including C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ ) via one, two or three (R ₁₁ ) group substitution. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C _1-6 alkyl and C _{1 -6} haloalkyl. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen and C _1-6 alkyl. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are hydrogen. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is hydrogen and R ₈ is -CH ₃ . The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is -CH ₃ and R ₈ is hydrogen. Such as the compound of any one of claims 1 to 12, or its pharmaceutically acceptable salt or solvate, wherein R ₇ and R ₈ are -CH ₃ . The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a 4-, 5- or 6-membered cycloalkyl ring; 4 -, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or a 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring optionally substituted with one, two or three R ₁₄ groups. For example, the compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted benzene ring. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, - OR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ or -C(O)N(R ₁₀ )(R ₁₁ ). The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or - OH. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OH. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or - OR ₁₀ . The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, - OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). Such as the compound of any one of claims 1 to 24, or its pharmaceutically acceptable salt or solvate, wherein R ₃ is C _1-6 alkyl or C _1-6 haloalkyl. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or - OR ₁₀ . The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, - OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen or C _1-6 alkyl. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R _9a )(R _9b )-. Such as the compound of claim 30, or its pharmaceutically acceptable salt or solvate, wherein R _9a is selected from hydrogen, halogen and C _1-6 alkyl. Such as the compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein R _9a is hydrogen. For example, the compound of claim 30 or claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein R _9b is selected from hydrogen, halogen and -OH. Such as the compound of claim 33, or its pharmaceutically acceptable salt or solvate, wherein R _9b is -OH. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(O)-. A compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof: Formula (II); wherein: R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , - OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O )R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), - CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and - via one, two or three Substitution of N(R ₁₀ )(R ₁₁ ); or combination of R ₁ and R ₂ to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl Ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or a 6-membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; or R ₂ and R ₃ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5 - or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; or R ₃ and R ₄ combined to form 4 -, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- Or a 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring optionally via one, two or three R ₁₄ groups group substitution; or R ₄ and R ₅ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl group Ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene optionally substituted with one, two or three R ₁₄ groups; R ₆ is R _6a is selected from hydrogen, C _1-6 alkyl and C _3-6 cycloalkyl, wherein C _1-6 alkyl and C _3-6 cycloalkyl are optionally separated by one, two or three R ₁₄ groups Substitution; or R _6a and R ₁₅ together form a bridge of -CH ₂ - or -CH ₂ CH ₂ -; R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 hetero Aryl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _{The 1-9} heteroaryl group is optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) group substitution; or R ₇ and R ₈ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6- Membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or the benzene ring is optionally substituted by one, two or three R ₁₄ groups; each R ₁₀ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one or two Or three selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _{6- 10} aryl and C _1-9 heteroaryl groups are substituted; each R ₁₁ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₂ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₃ is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 Cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one, two or three selected from halogen, C _1-6 alkyl, C ₁ -Substitution of _-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl groups; Each R ₁₄ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N (R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ) , -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N( R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N( R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one, two or Three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ¹⁰ and -N(R ₁₀ )(R ₁₁ ) are substituted; each R ₁₅ is independently selected from Halogen, side oxygen group, -CN, C _1-6 alkyl, C 1-6 haloalkyl, C _2-6 alkenyl, _{C 2-6 alkynyl, C 3-6 cycloalkyl ,} C _2-9 Heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC( O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C (O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ ) (R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ ) C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), among which C _1-6 alkyl and C _2-6 alkenyl , C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected by one, two or three Substituted from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ); or two R ₁₅ together form -CH ₂ - or - CH ₂ CH ₂ - bridge; and n is 0, 1, 2, 3 or 4. A compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof: Formula (III); wherein: R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , - OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O )R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), - CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and - via one, two or three Substitution of N(R ₁₀ )(R ₁₁ ); or combination of R ₁ and R ₂ to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl Ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or a 6-membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; or R ₂ and R ₃ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5 - or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring optionally substituted with one, two or three R ₁₄ groups; or R ₃ and R ₄ combined to form 4 -, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- Or a 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring optionally via one, two or three R ₁₄ groups group substitution; or R ₄ and R ₅ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl group Ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene optionally substituted with one, two or three R ₁₄ groups; R ₆ is or ; R _6a is selected from hydrogen and C _1-6 alkyl optionally substituted by one, two or three R ₁₄ groups; R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _{1- 6} alkyl, C _1-6 haloalkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _{C 2-9 heterocycloalkyl} , C _6-10 aryl and C _1-9 heteroaryl, including C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, _{C 3-6 cycloalkyl, C 2-9 heterocycloalkyl ,} C _{6- 10} aryl and C _1-9 heteroaryl are optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N( R ₁₀ ) (R ₁₁ ) is substituted with a group; or R ₇ and R ₈ are combined to form a 4-, 5- or 6-membered cycloalkyl ring; a 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or 6-membered heterocycloalkyl ring; 5- or 6 -membered heteroaryl ring; or the benzene ring is optionally substituted with one, two or three R ₁₄ groups; each R ₁₀ is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, where C _1-6 Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl as appropriate With one, two or three selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl Substituted with groups of C _6-10 aryl and C _1-9 heteroaryl; each R ₁₁ is independently selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₂ is independently selected Selected from hydrogen, C _1-6 alkyl and C _1-6 haloalkyl; each R ₁₃ is independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3- 6} cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, among which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl, optionally with one, two or three selected from halogen, C _1-6 Alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl Substituted with a group; each R ₁₄ is independently selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 Cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C( O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O) OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S( O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkane base, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl as appropriate. One, two or three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) are substituted; each R ₁₅ is independently selected from halogen, side oxygen group, -CN, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl , C _2-9 heterocycloalkyl, C _6-10 aryl, C _1-9 heteroaryl, -OR ₁₀ , -SR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ , -OC(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)OR ₁₃ , -N(R ₁₂ )S(O) ₂ R ₁₃ , -C(O)R ₁₃ , -S(O)R ₁₃ , -OC(O)R ₁₃ , -C(O)N(R ₁₀ )(R ₁₁ ), -C(O)C(O)N(R ₁₀ )(R ₁₁ ), -N(R ₁₂ )C(O)R ₁₃ , -S(O) ₂ R ₁₃ , -S(O) ₂ N(R ₁₀ )(R ₁₁ )-, S(=O)(=NH)N(R ₁₀ )(R ₁₁ ), -CH ₂ C(O)N(R ₁₀ )(R ₁₁ ), -CH ₂ N(R ₁₂ )C(O)R ₁₃ , -CH ₂ S(O) ₂ R ₁₃ and -CH ₂ S(O) ₂ N(R ₁₀ )(R ₁₁ ), wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl are optionally separated by one or two One or three groups selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ )(R ₁₁ ) are substituted; and n is 0, 1, 2, 3 or 4. Such as the compound of claim 36 or claim 37, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . The compound of any one of claims 36 to 38, or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is C _1-6 optionally substituted with one, two or three R ₁₄ groups alkyl. Such as the compound of any one of claims 36 to 39, or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is an unsubstituted C _1-6 alkyl group. The compound of any one of claims 36 to 38, or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is -CH ₃ . Such as the compound of claim 36 or claim 37, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₆ is . The compound of any one of claims 36 to 42, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. Such as the compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein R _6a is selected from: The compound of any one of claims 36 to 44, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, -CN, C _1-6 alkyl , C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _{1- 9} heteroaryl, including C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _2-9 heterocycloalkyl, C _6-10 aryl and C _1-9 heteroaryl optionally selected from halogen, -CN, C _1-6 alkyl, C _1-6 haloalkyl, -OR ₁₀ and -N(R ₁₀ ) via one, two or three (R ₁₁ ) group substitution. The compound of any one of claims 36 to 45, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C _1-6 alkyl and C _{1 -6} haloalkyl. The compound of any one of claims 36 to 46, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are each independently selected from hydrogen and C _1-6 alkyl. For example, the compound of any one of claims 36 to 47, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are hydrogen. The compound of any one of claims 36 to 47, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is hydrogen and R ₈ is -CH ₃ . The compound of any one of claims 36 to 47, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ is -CH ₃ and R ₈ is hydrogen. For example, the compound of any one of claims 36 to 47, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ are -CH ₃ . The compound of any one of claims 36 to 44, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form a 4-, 5- or 6-membered cycloalkyl ring; 4 -, 5- or 6-membered heterocycloalkyl ring; 5- or 6-membered heteroaryl ring; or benzene ring, wherein the 4-, 5- or 6-membered cycloalkyl ring; 4-, 5- or a 6-membered heterocycloalkyl ring; a 5- or 6-membered heteroaryl ring; or a benzene ring optionally substituted with one, two or three R ₁₄ groups. For example, the compound of claim 52, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₇ and R ₈ combine to form an unsubstituted benzene ring. The compound of any one of claims 36 to 53, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, - OR ₁₀ , -N(R ₁₀ )(R ₁₁ ), -C(O)OR ₁₀ or -C(O)N(R ₁₀ )(R ₁₁ ). The compound of any one of claims 36 to 54, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or - OH. The compound of any one of claims 36 to 55, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₁ is -OH. The compound of any one of claims 36 to 56, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or - OR ₁₀ . The compound of any one of claims 36 to 57, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₂ is hydrogen. The compound of any one of claims 36 to 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, - OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). Such as the compound of any one of claims 36 to 59, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₃ is C _1-6 alkyl or C _1-6 haloalkyl. The compound of any one of claims 36 to 60, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl or - OR ₁₀ . The compound of any one of claims 36 to 61, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₄ is hydrogen. Such as the compound of any one of claims 36 to 62, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, - OR ₁₀ or -N(R ₁₀ )(R ₁₁ ). The compound of any one of claims 36 to 63, or a pharmaceutically acceptable salt or solvate thereof, wherein R ₅ is hydrogen or C _1-6 alkyl. A compound selected from: or its pharmaceutically acceptable salt or solvate. A compound selected from: or its pharmaceutically acceptable salt or solvate. A pharmaceutical composition comprising a compound according to any one of claims 1 to 66 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. A method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt or solvate thereof. The method of claim 68, wherein the metabolic disease is selected from the group consisting of type 2 diabetes, atherosclerosis, obesity and gout. A method of treating liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt or solvate thereof. The method of claim 70, wherein the liver disease is selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis and cirrhosis. A method of treating lung disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt or solvate thereof. The method of claim 72, wherein the lung disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis. A method of treating a central nervous system disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 66 or a pharmaceutically acceptable salt or solvate thereof. The method of claim 74, wherein the central nervous system disease is selected from the group consisting of Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Huntington's disease, traumatic brain injury, ischemic stroke and reperfusion, hemorrhagic stroke, epilepsy and depression. A method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 66 or a pharmaceutically acceptable salt thereof, or Solvates. The method of claim 76, wherein the inflammatory or autoimmune disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, inflammatory bowel disease, Crohn's disease, and ulcers colitis. A method of treating cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt or solvate thereof. The method of claim 78, wherein the cardiovascular disease is atherosclerosis or stroke.